Synthesis method of 5-methoxy-3-benzofuranone

Abstract

The invention provides a synthesis method of 5-methoxy-3-benzofuranone, which comprises the following steps: by taking 2-hydroxy-5-methoxyacetophenone as a raw material, firstly converting the 2-hydroxy-5-methoxyacetophenone into an intermediate 2 (2-bromo-1-(2-hydroxy-5-methoxyphenyl) ethanone), and converting the intermediate 2 into a target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder. According to the synthesis method, alkali is not used in key steps, and silica gel powder is used for replacing alkali, so that reaction post-treatment and purification are simple, the reaction and time cost is greatly reduced, and manufacturability amplification can be realized.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing 5-methoxy-3-benzofuranone. Background Art

[0002] The compound 5-methoxy-3-benzofuranone is an important molecular building block. In patent CN112174974A, 5-methoxy-3-benzofuranone is used as a key intermediate in the synthesis of 3,4-dihydro-2H-pyrano[3,2-b]benzofuran-2-one skeleton compound. The 3,4-dihydro-2H-pyrano[3,2-b]benzofuran-2-one skeleton compound has applications in anti-tumor, anti-leukemia, antibacterial, anti-inflammatory, anti-cancer, hypoglycemic, platelet aggregation inhibition and long-term memory promotion. In patent WO200 In 9 / 053444, 5-methoxy-3-benzofuranone is also used as a key intermediate in the synthesis of a 2,3-dihydrobenzofuran compound, which can treat or prevent melatonin-related diseases; in patent US2005 / 004162, 5-methoxy-3-benzofuranone is also used as a key intermediate in the synthesis of 3-piperidin-4-acyl-1H-indole and 3-(1,2,3,6-tetrahydropyridine-4-acyl)-1H-indole derivatives, which can prevent or treat serotonin disorders such as depression and anxiety. Therefore, it is of great significance to study the synthesis method of 5-methoxy-3-benzofuranone.

[0003] In the prior art, the compound 2-bromo-1-(2-hydroxy-5-methoxyphenyl)ethanone is converted into the compound 5-methoxy-3-benzofuranone under the action of a base, but the reaction yield is low and the post-treatment requires column chromatography purification, which has a high purification time cost and is not suitable for process scale-up. Summary of the invention

[0004] In view of the shortcomings of the synthesis method of 5-methoxy-3-benzofuranone in the prior art, the purpose of the present invention is to provide a synthesis method of 5-methoxy-3-benzofuranone, which has the advantages of simple post-treatment, ideal yield and suitability for process scale-up.

[0005] To achieve the above object, the present invention adopts the following technical solution:

[0006] A method for synthesizing 5-methoxy-3-benzofuranone, using 2-hydroxy-5-methoxyacetophenone as a raw material, first converting it into an intermediate 2 (2-bromo-1-(2-hydroxy-5-methoxyphenyl)ethanone), and then converting the intermediate 2 into a target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder. The synthetic route is as follows:

[0007]

[0008] Further, the synthesis method of the 5-methoxy-3-benzofuranone comprises the following steps:

[0009] (1) Compound 1, i.e., 2-hydroxy-5-methoxyacetophenone, is added to an organic solvent I, copper bromide is added, and the mixture is heated to reflux under the protection of an inert gas, and stirred to react for 10-36 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2;

[0010] (2) Add silica gel powder to water, add compound 2, and then add organic solvent II, and react at room temperature for 2-5 hours. After the reaction is completed, the reaction solution is post-treated to obtain the target compound 5-methoxy-3-benzofuranone.

[0011] Furthermore, in step (1), the organic solvent I is one or more of ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, methanol and 1,4-dioxane.

[0012] Furthermore, in step (1), the inert gas is selected from one or more of nitrogen or argon.

[0013] Furthermore, in step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:(5-40) in g / mL.

[0014] Furthermore, in step (1), the molar ratio of compound 1 to copper bromide is 1:(1-5).

[0015] Furthermore, in step (1), the post-treatment is filtering the reaction solution, collecting the filtrate, and spinning the filtrate to obtain a crude product, which is purified to obtain compound 2.

[0016] Furthermore, in step (1), the purification method is selected from one or more of beating, column chromatography, recrystallization or distillation.

[0017] Furthermore, in step (2), the organic solvent II is acetonitrile or methanol or tetrahydrofuran or N,N-dimethylformamide or dimethyl sulfoxide.

[0018] Furthermore, in step (2), the mass ratio of the compound 2 to the silica gel powder is 1:(5-15).

[0019] Furthermore, in step (2), the post-treatment is to add methyl tert-butyl ether to the reaction solution and stir, wait for the silica gel powder to precipitate, then filter, collect the filtrate, wash the filtrate with water, wash with saturated brine, and spin dry to obtain a crude product, which is purified to obtain the target compound 5-methoxy-3-benzofuranone.

[0020] Furthermore, in step (2), the purification method is one or more of beating, column chromatography, recrystallization or distillation.

[0021] Compared with the prior art, the beneficial technical effects of the present invention are:

[0022] The present invention provides a method for synthesizing 5-methoxy-3-benzofuranone, wherein 2-hydroxy-5-methoxyacetophenone is used as a raw material, and is first converted into an intermediate 2 (2-bromo-1-(2-hydroxy-5-methoxyphenyl)ethanone), and the intermediate 2 is converted into a target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder. In the key step of the synthesis method, silica gel powder is used instead of alkali, so that the post-reaction treatment and purification are simple, the reaction and time costs are greatly reduced, and process amplification can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Attached Figure 1 This is the H NMR spectrum of 5-methoxy-3-benzofuranone in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] In order to make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be described clearly and completely in conjunction with the drawings of the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of them. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be the common meanings understood by people with ordinary skills in the field to which the present invention belongs.

[0025] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0026] The following example synthesizes 5-methoxy-3-benzofuranone. 2-Hydroxy-5-methoxyacetophenone is used as a raw material, which is first converted into an intermediate 2 (2-bromo-1-(2-hydroxy-5-methoxyphenyl)ethanone). Intermediate 2 is converted into the target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder. The synthetic route is as follows:

[0027]

[0028] The technical solution of the present invention is further explained below by way of embodiments.

[0029] Example 1

[0030] In this example, the compound 5-methoxy-3-benzofuranone was synthesized by the following steps:

[0031] (1) Compound 1, 2-hydroxy-5-methoxyacetophenone (200.00 g, 1.20 mol, 1.0 eq) was added to a mixed organic solvent of ethyl acetate (1.0 L) and chloroform (1.0 L), copper bromide (510.75 g, 2.29 mol, 1.90 eq) was added, and the mixture was heated to reflux under the protection of inert gas nitrogen, and stirred for reaction for 12 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (1.0 L), the filtrate was collected, and the filtrate was spin-dried to obtain a crude product, the crude product was slurried with petroleum ether, filtered, the solid was collected, and dried to obtain compound 2 (mass 281.20 g, purity 96%, yield 92%).

[0032] (2) Add silica gel powder (2000.00 g) to water (2.0 L), add compound 2 (200.00 g, 816.09 mmol, 1.0 eq), and then add acetonitrile (1.0 L), and react at 25° C. for 2 hours. After the reaction is completed, add methyl tert-butyl ether (5.0 L) to the reaction solution and stir, wait for the silica gel powder to precipitate, then filter, collect the filtrate, wash the filtrate with water, wash with saturated brine, and spin dry to obtain a crude product. The crude product is slurried with petroleum ether, filtered, the solid is collected, and dried to obtain the target compound 5-methoxy-3-benzofuranone (mass 131.10 g, purity 98%, yield 96%).

[0033] The H NMR spectrum of the obtained compound 3 (5-methoxy-3-benzofuranone) is as follows: Figure 1 The characterization data are as follows:

[0034] 1 H NMR (400MHz, cdcl3) δ7.29–7.17(m,1H),7.16–6.87(m,2H),4.64(s,2H),3.80(s,3H).

[0035] Embodiment 2-7

[0036] Example 2-7 is the same as Example 1, except that the amount of silica gel powder, organic solvent II, reaction temperature and reaction time used in step (2) are adjusted, as shown in Table 1.

[0037] Through Examples 1-7, the effects of various reaction conditions on the reaction yield in the synthesis of the target compound 3 (5-methoxy-3-benzofuranone) were verified. The results are shown in Table 1.

[0038] Table 1: Synthesis conditions and results of the examples

[0039]

[0040] Combined with Table 1, we can see that:

[0041] Comparing Examples 1-3, when the mass ratio of compound 2 to silica gel powder is 1:10, the reaction effect is already better.

[0042] Comparing Examples 1, 4-5, the reaction can be carried out in the solvents of acetonitrile, dichloromethane and acetone, among which acetonitrile is more effective as a solvent.

[0043] Comparing Examples 1 and 6, when the reaction temperature is 25°C, the reaction effect has reached the best.

[0044] Comparing Examples 1 and 7, the reaction time is 2 h, and the reaction effect has reached the best.

[0045] The above is a preferred embodiment of the present invention, but the present invention should not be limited to the contents disclosed in the embodiment. Therefore, any equivalent or modification completed without departing from the spirit disclosed in the present invention shall fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 5-methoxy-3-benzofuranone, characterized in that: 2-Hydroxy-5-methoxyacetophenone is used as a raw material, and is first converted into intermediate 2 (2-bromo-1-(2-hydroxy-5-methoxyphenyl)ethanone). Intermediate 2 is converted into target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder. The synthetic route is as follows:

2. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 1, characterized in that: The following steps are involved: (1) Compound 1, i.e., 2-hydroxy-5-methoxyacetophenone, is added to an organic solvent I, and then copper bromide is added. Under the protection of an inert gas, the mixture is heated to reflux and stirred for reaction for 10-36 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2; (2) Add silica gel powder to water, add compound 2, and then add organic solvent II, and react at room temperature for 2-5 hours. After the reaction is completed, the reaction solution is post-treated to obtain the target compound 3, namely 5-methoxy-3-benzofuranone.

3. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that: In step (1), the organic solvent I is one or more of ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, methanol, or 1,4-dioxane.

4. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that: In step (1), the inert gas is one or more of nitrogen or argon.

5. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that: In step (1): The mass volume ratio of the compound 1 to the organic solvent I is 1:(5-40) g / mL; The molar ratio of the compound 1 to copper bromide is 1:(1-5).

6. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that: In step (1), the post-treatment is to filter the reaction solution, collect the filtrate, spin-dry the filtrate to obtain a crude product, and purify the crude product to obtain compound 2.

7. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 6, characterized in that: In step (1), the purification method is one or more of beating, column chromatography, recrystallization or distillation.

8. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that: In step (2), the organic solvent II is acetonitrile or methanol or tetrahydrofuran or N,N-dimethylformamide or dimethyl sulfoxide.

9. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that: In step (2), the mass ratio of the compound 2 to the silica gel powder is 1:(5-15).

10. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that: In step (2), the post-treatment is to add methyl tert-butyl ether to the reaction solution and stir, wait for the silica gel powder to precipitate, then filter, collect the filtrate, wash the filtrate with water, wash with saturated brine, and spin dry to obtain a crude product, which is purified to obtain the target compound 5-methoxy-3-benzofuranone.

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