Synthesis method of 6-bromo-3-benzofuranone

Abstract

The invention discloses a synthesis method of 6-bromine-3-benzofuranone. The synthesis method comprises the following steps of: adding a catalyst; the synthesis method comprises the following steps: (1) taking a compound 1 as an initial raw material, and carrying out bromination reaction to prepare a compound 2; and (2) carrying out cyclization reaction on the compound 2 under the action of 335 weak base gel type anion resin to obtain a target product, namely the 6-bromo-3-benzofuranone. In the key steps of the synthesis method, 335 weak base gel type anion resin is creatively used, so that the reaction post-treatment and purification are simple, the yield is high, the reaction and time cost is greatly reduced, and the process amplification production can be realized.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 6-bromo-3-benzofuranone. Background Art

[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. The JAK kinase inhibitors can inhibit the biological activities of JAK1, JAK2, JAK3 and TYK2 kinases involved in various signal transductions, and can effectively treat various inflammatory diseases and various diseases driven by JAK-mediated signal transduction in the clinic. The application prospects are very broad; in patent WO2019 / 144041, 6-bromo-3-benzofuranone is used as a key intermediate in the synthesis of JAK kinase inhibitors. As a key intermediate, benzofuranone is used in the synthesis of dihydrobenzofuran and ninhydrin analogs as cardiomyoma inhibitors; in patent WO2024 / 027370, 6-bromo-3-benzofuranone is used as a key intermediate in the synthesis of a nitrogen-containing tri-fused 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 HPKI inhibitors, which can be used to treat HPK1-mediated diseases such as cancer.

[0003] In the prior art, regarding the synthesis of 6-bromo-3-benzofuranone, the compound 2-bromo-1-(4-bromo-2-hydroxyphenyl)ethan-1-one is usually converted into the compound 6-bromo-3-benzofuranone under the action of triethylamine, but the reaction yield is low and is not suitable for process scale-up. Therefore, it is of great significance to develop a simple, efficient and high-yield synthesis method of 6-bromo-3-benzofuranone. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing 6-bromo-3-benzofuranone. The method provided by the present invention has the advantages of simple post-treatment, high yield and suitability for process amplification.

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

[0006] A method for synthesizing 6-bromo-3-benzofuranone, wherein the method is carried out according to the following process:

[0007] The specific steps include:

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

[0009] (2) Compound 2 is subjected to a cyclization reaction under the action of 335 weak base gel anion 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:

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

[0012] Furthermore, 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; and the mass volume ratio of the compound 1 to the organic solvent I is 1:5-40 g / mL.

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

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

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

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

[0017] Furthermore, 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 g / mL 1:5 to 40.

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

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

[0020] The beneficial technical effects of the present invention are:

[0021] The invention provides a method for synthesizing 6-bromo-3-benzofuranone. 1-(4-bromo-2-hydroxyphenyl)ethanone is used as a raw material, which is first converted into an intermediate 2-bromo-1-(4-bromo-2-hydroxyphenyl)ethan-1-one. The intermediate is then converted into a target compound 3 (6-bromo-3-benzofuranone) under the action of a 335 weak base gel-type anion resin.

[0022] The synthesis method of the present invention creatively uses 335 weak base gel-type anion resin in the key step, so that the post-reaction treatment and purification are simpler, the reaction and time costs are greatly reduced, and the process scale-up production can be realized. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the H NMR spectrum of 6-bromo-3-benzofuranone synthesized in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.

[0025] The brand of 335 weak base gel anion resin used in the following examples is Adamas, CAS number: N#A221400.

[0026] Example 1

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

[0028] (1) 1-(4-bromo-2-hydroxyphenyl)ethanone (200.00 g, 930.03 mmol, 1.0 eq) was added to a mixed organic solvent of ethyl acetate (1.0 L) and chloroform (1.0 L), and copper bromide (311.59 g, 1.40 mol, 1.50 eq) was added. Under nitrogen protection, the mixture was heated to reflux and stirred at 70° C. for 12 h. 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 dried to obtain a crude product. The crude product was slurried 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 335 weak base gel anion resin (2000.00 g) was slowly added, and the mixture was reacted 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, the filtrate was washed with water, washed with saturated brine, and dried to obtain a 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 H NMR spectrum of the obtained compound 3 (6-bromo-3-benzofuranone) is as follows: Figure 1 The characterization data are 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, except that the amount of 335 weak base gel-type anion resin used in step (2) of Example 2 is 3000 g (i.e., the mass ratio of compound 2 to anion resin is 1:15), and the rest of the contents remain 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 of the contents remain 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 of the contents remain 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 5 h, 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, except that the amount of 335 weak base gel-type anion resin used in step (2) of Comparative Example 1 is 1000 g (i.e., the mass ratio of compound 2 to anion resin is 1:5), and the rest of the contents remain 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 to replace acetonitrile in Example (1), and the rest of the contents remain unchanged. The yield of 6-bromo-3-benzofuranone is shown in Table 1.

[0044] Table 1 Synthesis conditions of various embodiments / comparative examples and yield results of 6-bromo-3-benzofuranone

[0045]

[0046] It can be seen from the results in Table 1 that compared with Comparative Example 1, Examples 1-2 of the present invention optimize the relative amounts of Compound 2 and 335 weak base gel-type anion resin, and significantly improve the yield of the target compound 6-bromo-3-benzofuranone. When the mass ratio of Compound 2 to 335 weak base gel-type anion resin is 1:10, the reaction effect is optimal.

[0047] It can be seen from the results of Example 1, Example 3 and Comparative Example 2 that when the organic solvent in the mixed solvent is acetonitrile, dichloromethane and acetone, the reaction can be carried out. The present 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 and 335 weak base gel-type anion resin. Among them, when the organic solvent is acetonitrile and dichloromethane, the reaction effect is better; when the organic solvent is acetonitrile, the reaction effect is the best.

[0048] The above is only 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 changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in 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 process: The specific steps include: (1) Compound 2 is prepared by bromination reaction using compound 1 as the starting material; (2) Compound 2 is subjected to a cyclization reaction under the action of 335 weak base gel anion 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: Compound 1 is added to organic solvent I, copper bromide is added, and the mixture is heated to reflux under the protection of an inert gas, and stirred for reaction. After the reaction is completed, the reaction solution is 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 volume ratio of the compound 1 to the organic solvent I is 1:5-40 g / mL.

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

5. The synthesis method according to claim 2, characterized in that The reaction temperature is 60-100° C. and the reaction time is 10-40 hours.

6. The synthesis method according to claim 1, characterized in that In step (2), the specific process of the cyclization reaction is: Compound 2 is added to a mixed solvent of water and organic solvent II, and 335 weak base gel-type anion resin is added to react. After the reaction is completed, the reaction solution is 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 the organic solvent II is 1 to 3:1; the mass volume ratio of the compound 2 to the mixed solvent is g / mL 1:5 to 40.

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

9. The synthesis method according to claim 6, characterized in that: The reaction temperature is 15-40°C and the reaction time is 2-5 hours.

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