A method for synthesizing 6-bromo-3-benzofuranone

Abstract

The application discloses a synthesis method of 6-bromo-3-benzofuranone. The synthesis method comprises the following steps: (1) taking compound 1 as a starting material, and preparing compound 2 through a bromination reaction; and (2) preparing the target product, i.e., the 6-bromo-3-benzofuranone, through a cyclization reaction of the compound 2 under the action of a 335 weak base gel type anion resin. In the key step of the synthesis method, the 335 weak base gel type anion resin is creatively used, so that the post-reaction treatment and purification are simple, the yield is high, the reaction and time costs are greatly reduced, and the process amplification production can be realized.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing 6-bromo-3-benzofuranone. Background Technology

[0002] The compound 6-bromo-3-benzofuranone is an important molecular building block. For example, in patent CN108341814A, 6-bromo-3-benzofuranone is used as a key intermediate in the synthesis of JAK kinase inhibitors. These JAK kinase inhibitors can inhibit the biological activity of JAK1, JAK2, JAK3, and TYK2 kinases involved in multiple signal transductions, and can effectively treat various inflammatory diseases and diseases driven by JAK-mediated signal transduction in clinical practice, showing great promise for application. In patent WO2019 / 144041, 6-bromo-3-benzofuranone... 6-Bromo-3-benzofuranone is used as a key intermediate in the synthesis of dihydrobenzofuran and ninhydrin analogs, which are inhibitors of cardiomyoma; in patent WO2024 / 027370, 6-bromo-3-benzofuranone is used as a key intermediate in the synthesis of a nitrogen-containing trifused ring PRMTS inhibitor, which can be used to treat or prevent PRMT5-mediated diseases; in patent WO2022 / 188735, 6-bromo-3-benzofuranone is used as a key intermediate in the synthesis of an HPKI inhibitor, which can be used to treat HPK1-mediated diseases such as cancer.

[0003] In existing technologies, the synthesis of 6-bromo-3-benzofuranone typically involves converting 2-bromo-1-(4-bromo-2-hydroxyphenyl)ethyl-1-one to 6-bromo-3-benzofuranone via the action of triethylamine. However, this reaction has low yields and is not suitable for large-scale production. Therefore, developing a simple, efficient, and high-yield synthetic method for 6-bromo-3-benzofuranone is of great significance. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for synthesizing 6-bromo-3-benzofuranone. The synthetic method provided by this invention has the advantages of simple post-processing, high yield, and suitability for process scale-up.

[0005] The technical solution of the present invention is as follows:

[0006] A method for synthesizing 6-bromo-3-benzofuranone, the method comprising the following steps:

[0007] Specifically, the steps include the following:

[0008] (1) Compound 2 was prepared by bromination reaction using compound 1 as the starting material;

[0009] (2) Compound 2 was cyclized in the presence of 335 weak base gel anion exchange resin to obtain the target product, namely the 6-bromo-3-benzofuranone.

[0010] Furthermore, in step (1), the specific process of the bromination reaction is as follows:

[0011] Compound 1 was added to organic solvent I, copper bromide was added, and the mixture was heated to reflux under inert gas protection. The mixture was stirred and reacted. After the reaction was completed, the reaction solution was post-treated to obtain compound 2.

[0012] Further, the organic solvent I is selected from one or more of ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, methanol, and 1,4-dioxane; the mass-to-volume ratio of compound 1 to organic solvent I is 1:5-40 (g / mL).

[0013] Furthermore, the molar ratio of compound 1 to copper bromide is 1:1 to 5.

[0014] Furthermore, the reaction temperature is 60–100°C, and the time is 10–40 h.

[0015] Furthermore, in step (2), the specific process of the cyclization reaction is as follows:

[0016] Compound 2 was added to a mixed solvent of water and organic solvent II, and then 335 weak base gel-type anion exchange resin was added to carry out the reaction. After the reaction was completed, the reaction solution was post-treated to obtain the target compound 6-bromo-3-benzofuranone.

[0017] Further, the organic solvent II is selected from one or more of acetonitrile and dichloromethane; in the mixed solvent, the volume ratio of water to organic solvent II is 1 to 3:1; the mass-volume ratio of compound 2 to the mixed solvent is 1:5 to 40 g / mL.

[0018] Furthermore, the mass ratio of compound 2 to 335 weak base gel-type anion exchange resin is 1:10-15.

[0019] Furthermore, the reaction temperature is 15–40°C, and the reaction time is 2–5 hours.

[0020] The beneficial technical effects of this invention are as follows:

[0021] This invention provides a method for synthesizing 6-bromo-3-benzofuranone, using 1-(4-bromo-2-hydroxyphenyl)ethyl ketone as a raw material, first converting it into the intermediate 2-bromo-1-(4-bromo-2-hydroxyphenyl)ethyl-1-ketone, and then converting the intermediate into the target compound 3 (6-bromo-3-benzofuranone) under the action of 335 weak base gel anion exchange resin.

[0022] The synthesis method of this invention creatively uses 335 weak base gel-type anion exchange resin in key steps, which simplifies post-reaction processing and purification, greatly reduces reaction and time costs, and enables large-scale production. Attached Figure Description

[0023] Figure 1 The image shows the 1H NMR spectrum of 6-bromo-3-benzofuranone synthesized in Example 1 of this invention. Detailed Implementation

[0024] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0025] The 335 weak base gel anion exchange resin used in the following examples is from Adamas, CAS No.: N#A221400.

[0026] Example 1

[0027] A method for synthesizing 6-bromo-3-benzofuranone includes the following steps:

[0028] (1) 200.00 g, 930.03 mmol, 1.0 eq of 1-(4-bromo-2-hydroxyphenyl) ethyl ketone was added to a mixed organic solvent of ethyl acetate (1.0 L) and chloroform (1.0 L), and then copper bromide (311.59 g, 1.40 mol, 1.50 eq) was added. The mixture was heated to reflux under nitrogen protection and stirred at 70 °C for 12 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (1.0 L), the filtrate was collected, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was pulped to obtain 264.30 g of compound 2 (purity 96%, yield 93%).

[0029] (2) Compound 2 (200.00 g, 680.41 mmol, 1.0 eq) was added to a mixed solvent of water (1.0 L) and acetonitrile (1.0 L), and 2000.00 g of 335 weak base gel-type anion exchange resin was slowly added. The reaction was carried out at 25 °C for 2 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with methyl tert-butyl ether (1.0 L), the filtrate was collected, and the filtrate was washed with water and saturated brine. The solution was then evaporated to dryness to obtain the crude product. The crude product was pulped to obtain 141.90 g of the target compound 6-bromo-3-benzofuranone (purity 98%, yield 96%).

[0030] The 1H NMR spectrum of the obtained compound 3 (6-bromo-3-benzofuranone) is as follows: Figure 1 As shown, the characterization data is as follows:

[0031] 1H NMR (400MHz, CdCl3) δ7.53 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.64 (s, 2H).

[0032] Example 2

[0033] The synthesis method of Example 2 is basically the same as that of Example 1. The only difference is that the amount of 335 weak base gel anion exchange resin used in step (2) of Example 2 is 3000g (that is, the mass ratio of compound 2 to anion exchange resin is 1:15). The rest remains unchanged. The yield of 6-bromo-3-benzofuranone is shown in Table 1.

[0034] Example 3

[0035] The synthesis method of Example 3 is basically the same as that of Example 1, except that dichloromethane is used in step (2) of Example 3 to replace acetonitrile in Example (1), and the rest remains unchanged. The yield of 6-bromo-3-benzofuranone is shown in Table 1.

[0036] Example 4

[0037] The synthesis method of Example 4 is basically the same as that of Example 1, except that the reaction temperature in step (2) of Example 4 is 40°C, and the rest remains unchanged. The yield of 6-bromo-3-benzofuranone is shown in Table 1.

[0038] Example 5

[0039] The synthesis method of Example 5 is basically the same as that of Example 1, except that the reaction time in step (2) of Example 5 is 5h, and the rest remains unchanged. The yield of 6-bromo-3-benzofuranone is shown in Table 1.

[0040] Comparative Example 1

[0041] The synthesis method of Comparative Example 1 is basically the same as that of Example 1. The only difference is that the amount of 335 weak base gel anion exchange resin used in step (2) of Comparative Example 1 is 1000g (that is, the mass ratio of compound 2 to anion exchange resin is 1:5). The rest remains unchanged. The yield of 6-bromo-3-benzofuranone is shown in Table 1.

[0042] Comparative Example 2

[0043] The synthesis method of Comparative Example 2 is basically the same as that of Example 1, except that acetone is used in step (2) of Comparative Example 2 instead of acetonitrile in Example (1), and the rest remains unchanged. The yield of 6-bromo-3-benzofuranone is shown in Table 1.

[0044] Table 1 Synthesis conditions and yield results of 6-bromo-3-benzofuranone for each example / comparative example

[0045]

[0046] As can be seen from the results in Table 1, compared with Comparative Example 1, the present invention optimized the relative amounts of compound 2 and 335 weak base gel-type anion exchange resin in Examples 1-2, which significantly improved the yield of the target compound 6-bromo-3-benzofuranone. The reaction effect was optimal when the mass ratio of compound 2 to 335 weak base gel-type anion exchange resin was 1:10.

[0047] The results of Examples 1, 3, and Comparative Example 2 show that the reaction can proceed when the organic solvent in the mixed solvent is acetonitrile, dichloromethane, or acetone. This invention significantly improves the yield of the target compound 6-bromo-3-benzofuranone by optimizing the type of organic solvent in the reaction of compound 2 with 335 weak base gel-type anion exchange resin. Among these, the reaction effect is better when the organic solvent is acetonitrile or dichloromethane, and the reaction effect is optimal when the organic solvent is acetonitrile.

[0048] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and variations that are directly derived or conceived by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 6-bromo-3-benzofuranone, characterized in that, The synthesis method is carried out according to the following procedure: Specifically, the steps include the following: (1) Compound 2 was prepared by bromination reaction using compound 1 as the starting material; (2) Compound 2 was cyclized in the presence of 335 weak base gel anion exchange resin to obtain the target product, namely the 6-bromo-3-benzofuranone.

2. The synthesis method according to claim 1, characterized in that, In step (1), the specific process of the bromination reaction is as follows: Compound 1 was added to organic solvent I, copper bromide was added, and the mixture was heated to reflux under inert gas protection. The mixture was stirred and reacted. After the reaction was completed, the reaction solution was post-treated to obtain compound 2.

3. The synthesis method according to claim 2, characterized in that, The organic solvent I is selected from one or more of ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, methanol, and 1,4-dioxane; the mass-to-volume ratio of compound 1 to organic solvent I is 1:5-40 (g / mL).

4. The synthesis method according to claim 2, characterized in that, The molar ratio of compound 1 to copper bromide is 1:1 to 5.

5. The synthesis method according to claim 2, characterized in that, The reaction is carried out at a temperature of 60–100°C for a time of 10–40 h.

6. The synthesis method according to claim 1, characterized in that, In step (2), the specific process of the cyclization reaction is as follows: Compound 2 was added to a mixed solvent of water and organic solvent II, and then 335 weak base gel-type anion exchange resin was added to carry out the reaction. After the reaction was completed, the reaction solution was post-treated to obtain the target compound 6-bromo-3-benzofuranone.

7. The synthesis method according to claim 6, characterized in that, The organic solvent II is selected from one or more of acetonitrile and dichloromethane; in the mixed solvent, the volume ratio of water to organic solvent II is 1 to 3:1; the mass-volume ratio of compound 2 to the mixed solvent is 1:5 to 40 g / mL.

8. The synthesis method according to claim 6, characterized in that, The mass ratio of compound 2 to 335 weak base gel-type anion exchange resin is 1:10-15.

9. The synthesis method according to claim 6, characterized in that, The reaction is carried out at a temperature of 15–40°C for 2–5 hours.

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