Preparation method of 5-bromo-4-chloro-1H-indole-3-alcohol
The preparation process of 5-bromo-4-chloro-1H-indole-3-ol was simplified by a four-step reaction involving bromination, ammoniation, cyclization, and hydrolysis, solving the problems of cumbersome steps and high cost in existing technologies, and realizing efficient and low-cost industrial production.
Patent Information
- Application Number
- CN202511172056.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-21
- Publication Date
- 2025-11-28
AI Technical Summary
Existing methods for preparing 5-bromo-4-chloro-1H-indole-3-ol are cumbersome, costly, and difficult to scale up for industrial production.
5-Bromo-4-chloro-1H-indole-3-ol was synthesized by a four-step reaction involving bromination, ammoniation, cyclization, and hydrolysis of 2-chloro-6-fluorobenzoic acid with a catalyst, followed by ammoniation with glycine in the presence of an organic base, cyclization, and hydrolysis.
It simplifies the reaction steps, reduces costs, increases yield, and is suitable for industrial production.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of 5-bromo-4-chloro-1H-indol-3-ol. BACKGROUND
[0002] 5-bromo-4-chloro-1H-indol-3-ol is an important biochemical reagent, which can be oxidized to generate indigo dye (λmax=615nm) after enzymatic reaction in neuraminidase detection, and the sensitivity can reach 0.01 U / mL; it can also be used as a key intermediate of color developing substrate of hydrolytic enzymes such as neuraminidase and beta-galactosidase.
[0003] In recent years, the application of 5-bromo-4-chloro-1H-indol-3-ol has been expanded from the traditional diagnostic field to the fields of drug research and development, material science and other frontiers. The existing technology (DOI: 10.1039 / c4ob02248c) discloses that the current synthesis method is to obtain the target product 5-bromo-4-chloro-1H-indol-3-ol from 2-chloro-6-fluorobenzaldehyde through cyanation, amination, bromination, cyano ester hydrolysis, cyclization and ester amide hydrolysis, which is relatively cumbersome.
[0004] Therefore, it is urgent to develop a preparation method of 5-bromo-4-chloro-1H-indol-3-ol with simple steps and low cost. SUMMARY
[0005] In view of the deficiencies of the prior art, the purpose of the present application is to provide a preparation method of 5-bromo-4-chloro-1H-indol-3-ol. The preparation method provided by the present application has simple raw materials, simple preparation method, low cost and high yield.
[0006] In order to achieve the purpose of the present application, the following technical solutions are adopted:
[0007] The present application provides a preparation method of 5-bromo-4-chloro-1H-indol-3-ol, comprising the following steps:
[0008] S1. 2-chloro-6-fluorobenzoic acid is subjected to bromination reaction under the action of a catalyst to obtain an intermediate 1;
[0009] S2. The intermediate 1 and glycine are subjected to amination reaction under the action of an organic base to obtain an intermediate 2;
[0010] S3. The intermediate 2 and acetic anhydride are subjected to cyclization reaction under the action of an organic base in an inert gas atmosphere to obtain an intermediate 3;
[0011] S4. The intermediate 3 is subjected to hydrolysis reaction under alkaline conditions in an inert gas atmosphere to obtain the 5-bromo-4-chloro-1H-indol-3-ol;
[0012] The reaction route is as follows:
[0013]
[0014] Specifically, in the S1 step, the molar ratio of the 2-chloro-6-fluorobenzoic acid, the bromination agent, and the catalyst is 1:(1-1.3):(0.05-0.2).
[0015] Preferably, the bromination agent includes one of liquid bromine and NBS.
[0016] Specifically, in the S1 step, the temperature of the bromination reaction is 25-50°C, and the time is 12-24h; preferably, the temperature of the bromination reaction in step (1) can be 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, etc.; the time can be 12h, 14h, 16h, 18h, 20h, 22h, or 24h, etc., but is not limited to the above-mentioned values, and other values not mentioned in the above-mentioned value range are also applicable.
[0017] Preferably, the bromination reaction also needs to add a solvent, and the solvent includes one of glacial acetic acid and trifluoromethanesulfonic acid.
[0018] More preferably, the molar ratio of the 2-chloro-6-fluorobenzoic acid and the solvent is 1:(12-15).
[0019] Specifically, in the S1 step, the catalyst includes one of iron, iron bromide, and palladium acetate.
[0020] Preferably, the catalyst is palladium acetate, and the reaction needs to be carried out in an inert gas atmosphere.
[0021] Specifically, in the S2 step, the molar ratio of the intermediate 1, glycine, and the organic base is 1:(1.1-1.5):(3-7).
[0022] Preferably, the temperature of the amination reaction is 50-70°C, and the time is 4-8h; more preferably, the temperature of the amination reaction can be 50°C, 55°C, 60°C, 65°C, or 70°C, etc., and the time can be 4h, 5h, 6h, 7h, or 8h, etc., but is not limited to the above-mentioned values, and other values not mentioned in the above-mentioned value range are also applicable.
[0023] Specifically, in the S2 step, the organic base includes one of triethylamine and pyridine.
[0024] Preferably, the amination reaction also needs to add a solvent, and the solvent includes one of 1,4-dioxane, tetrahydrofuran, and DMF.
[0025] Specifically, in the S3 step, the molar ratio of the intermediate 2, acetic anhydride and the organic base is 1:(9-12):(8-12).
[0026] Preferably, the temperature of the cyclization reaction is 70-90 DEG C, and the time is 12-16h; preferably, the temperature of the cyclization reaction can be 70 DEG C, 75 DEG C, 80 DEG C, 85 DEG C or 90 DEG C, and the time can be 12h, 13h, 14h, 15h or 16h, but is not limited to the above listed values, and other values not listed in the above value range are also applicable.
[0027] Specifically, in the S3 step, the organic base includes one of trimethylamine, triethylamine and pyridine.
[0028] Specifically, in the S4 step, the molar ratio of the intermediate 3 and the base is 1:(12-15).
[0029] Specifically, in the S4 step, the temperature of the hydrolysis reaction is 80-90 DEG C, and the time is 0.5-1.5h; preferably, the temperature of the hydrolysis reaction can be 80 DEG C, 81 DEG C, 82 DEG C, 83 DEG C, 84 DEG C, 85 DEG C, 86 DEG C, 87 DEG C, 88 DEG C, 89 DEG C or 90 DEG C, and the time can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1.0h, 1.1h, 1.2h, 1.3h, 1.4h or 1.5h, but is not limited to the above listed values, and other values not listed in the above value range are also applicable.
[0030] Preferably, the base includes one of sodium hydroxide and potassium hydroxide.
[0031] Compared with the prior art, the present application has the following beneficial effects:
[0032] The present application provides a preparation method of 5-bromo-4-chloro-1H-indol-3-ol, which is a new method for synthesizing 5-bromo-4-chloro-1H-indol-3-ol from 2-chloro-6-fluorobenzoic acid through four steps of bromination, amination, cyclization and hydrolysis; compared with the previous process, the reaction process is optimized, the number of reaction steps is reduced, and the cost is controlled and industrial production is facilitated. DETAILED DESCRIPTION
[0033] In order to further illustrate the technical means adopted by the present application and its effects, the technical solutions of the present application will be further described below in combination with the preferred embodiments of the present application, but the present application is not limited in the scope of the embodiments.
[0034] A preparation method of 5-bromo-4-chloro-1H-indol-3-ol, comprising the following steps:
[0035] S1. 2-chloro-6-fluorobenzoic acid is subjected to bromination reaction with a brominating agent in the presence of a catalyst to obtain intermediate 1; the molar ratio of 2-chloro-6-fluorobenzoic acid, the brominating agent and the catalyst is 1: (1-1.3): (0.05-0.2); the bromination reaction is carried out at a temperature of 25-50℃ for 12-24h; the brominating agent includes one of liquid bromine and NBS; the catalyst includes one of iron, iron bromide and palladium acetate, preferably, the catalyst is palladium acetate, and the reaction is carried out in an inert gas atmosphere; the solvent includes one of glacial acetic acid and trifluoromethanesulfonic acid.
[0036] S2. Intermediate 1, glycine and a solvent are subjected to amination reaction in the presence of an organic base to obtain intermediate 2; the molar ratio of intermediate 1, glycine and the organic base is 1: (1.1-1.5): (3-7); the amination reaction is carried out at a temperature of 50-70℃ for 4-8h; the organic base includes one of triethylamine and pyridine; the solvent includes one of 1,4-dioxane, acetonitrile, tetrahydrofuran and DMF.
[0037] S3. Intermediate 2 and acetic anhydride are subjected to cyclization reaction in the presence of an organic base under an inert gas atmosphere to obtain intermediate 3; the molar ratio of intermediate 2, acetic anhydride and the organic base is 1: (9-12): (8-12); the cyclization reaction is carried out at a temperature of 70-90℃ for 12-16h; the organic base includes one of trimethylamine, triethylamine and pyridine.
[0038] S4. Intermediate 3 is subjected to hydrolysis reaction under alkaline conditions under an inert gas atmosphere to obtain 5-bromo-4-chloro-1H-indol-3-ol; the molar ratio of intermediate 3 and the base is 1: (12-15); the hydrolysis reaction is carried out at a temperature of 80-90℃ for 0.5-1.5h; the base includes one of sodium hydroxide and potassium hydroxide.
[0039] The reaction route is as follows:
[0040]
[0041] Example 1
[0042] The embodiment provides a preparation method of 5-bromo-4-chloro-1H-indol-3-ol, which comprises the following steps:
[0043] S1. In a reaction flask, 2-chloro-6-fluorobenzoic acid (14.9 g, 85.4 mmol) was dissolved in 70 mL of glacial acetic acid, and bromine (15.6 g, 98.2 mmol) was added dropwise to the solution over 5 minutes. Iron powder (478 mg, 8.5 mmol) was then added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was diluted with water and extracted with 50 mL of n-hexane three times. The combined extract was washed with 50 mL of an aqueous sodium thiosulfate solution (5%), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 16.9 g of intermediate 1 at a yield of 78.6%.
[0044] S2. In a reaction flask, 100 mL of 1,4-dioxane was added at room temperature, and intermediate 1 (10 g, 39.6 mmol), triethylamine (20.0 g, 198 mmol), and glycine (3.6 g, 47.5 mmol) were stirred and mixed. The mixture was then raised to 60°C and reacted for 6 h. After distilling off the reaction solvent, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) and concentrated under reduced pressure to obtain 11.2 g of intermediate 2 at a yield of 92.6%.
[0045] S3. Under a nitrogen atmosphere, acetic anhydride (110 mL, 1200 mmol) was added to a reaction flask, and triethylamine (170 mL, 1242 mmol) and intermediate 2 (35.9 g, 117 mmol) were slowly added at 0°C. After stirring at room temperature for 5 h, the mixture was raised to 80°C and further heated for 16 h. The reaction mixture was then cooled to 0°C and extracted with ethyl acetate (3 x 150 mL). The organic layer was washed with a brine solution, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 35.0 g of intermediate 3 at a yield of 91.1%.
[0046] S4. Under a nitrogen atmosphere, intermediate 3 (10 g, 30.4 mmol) was dissolved in completely deoxygenated water (200 mL), and sodium hydroxide (16 g, 401 mmol) was added. The mixture was stirred at 85°C for 1 h. The reaction solution was then cooled to <5°C, and 30 mL of an aqueous citric acid solution (0.5N) was added dropwise while maintaining the reaction temperature at <5°C. Then, NaCl (30 g) was added, and the reaction solution was cooled to 0°C and stirred for 1 h. The greenish-yellow solid product was collected by suction filtration, washed with 30 mL of an aqueous citric acid solution (0.5N) and pure water, and dried under vacuum to obtain 7.0 g of the product, i.e., 5-bromo-4-chloro-1H-indol-3-ol, at a yield of 94.2%.
[0047] Example 2
[0048] The present example provides a method of preparing 5-bromo-4-chloro-1H-indol-3-ol, including the following steps:
[0049] S1. In a reaction flask, 2-chloro-6-fluorobenzoic acid (14.9 g, 85.4 mmol) was dissolved in 70 mL of glacial acetic acid, and bromine (13.5 g, 85.4 mmol) was added dropwise to the solution over 5 minutes. Iron powder (240 mg, 4.3 mmol) was then added, and the mixture was stirred at 35 °C for 12 h. After the reaction was completed, the reaction solution was diluted with water and extracted with 50 mL of n-hexane three times. The combined extract was washed with 50 mL of an aqueous sodium thiosulfate solution (5%), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 15.6 g of intermediate 1 at a yield of 72.7%.
[0050] S2. At room temperature, 100 mL of 1,4-dioxane was added to a reaction flask, and intermediate 1 (10 g, 39.6 mmol), triethylamine (17 mL, 119 mmol), and glycine (3.3 g, 43.6 mmol) were stirred and mixed. The mixture was then raised to 50 °C and reacted for 8 h. After distilling off the reaction solvent, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) and concentrated under reduced pressure to obtain 10.8 g of intermediate 2 at a yield of 89.5%.
[0051] S3. Under a nitrogen atmosphere, acetic anhydride (96.5 mL, 1053 mmol) was added to a reaction flask, and triethylamine (128 mL, 936 mmol) and intermediate 2 (35.9 g, 117 mmol) were slowly added at 0 °C. After stirring at room temperature for 5 h, the mixture was raised to 70 °C and further heated for 14 h. The reaction mixture was then cooled to 0 °C and extracted with ethyl acetate (3 x 150 mL). The organic layer was washed with a brine solution, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 33.3 g of intermediate 3 at a yield of 86.7%.
[0052] S4. Under a nitrogen atmosphere, intermediate 3 (10 g, 30.4 mmol) was dissolved in completely deoxygenated water (200 mL), and sodium hydroxide (14.6 g, 365 mmol) was added. The mixture was stirred at 80 °C for 1.5 h. The reaction solution was then cooled to <5 °C, and 30 mL of an aqueous citric acid solution (0.5 N) was added dropwise while maintaining the reaction temperature at <5 °C. Then, NaCl (30 g) was added, and the reaction solution was cooled to 0 °C and stirred for 1 h. The greenish-yellow solid product was collected by suction filtration, washed with 30 mL of an aqueous citric acid solution (0.5 N) and pure water, and dried under vacuum to obtain 6.7 g of the product, i.e., 5-bromo-4-chloro-1H-indol-3-ol, at a yield of 91.2%.
[0053] Example 3
[0054] This example provides a method of preparing 5-bromo-4-chloro-1H-indol-3-ol, including the following steps:
[0055] S1. In a reaction flask, 2-chloro-6-fluorobenzoic acid (14.9 g, 85.4 mmol) was dissolved in 70 mL of glacial acetic acid, and bromine (17.6 g, 111 mmol) was added dropwise to the solution over 5 minutes. Iron powder (956 mg, 17 mmol) was then added, and the mixture was stirred at 50 °C for 18 h. After the reaction was completed, the reaction solution was diluted with water and extracted with 50 mL of n-hexane three times. The combined extract was washed with 50 mL of an aqueous sodium thiosulfate solution (5%), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 16.3 g of intermediate 1 at a yield of 75.9%.
[0056] S2. In a reaction flask, 100 mL of 1,4-dioxane was added at room temperature, and intermediate 1 (10 g, 39.6 mmol), triethylamine (28.0 g, 277.2 mmol), and glycine (4.5 g, 59.4 mmol) were stirred and mixed. The mixture was then raised to 50 °C and reacted for 8 h. After distilling off the reaction solvent, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) and concentrated under reduced pressure to obtain 11.1 g of intermediate 2 at a yield of 91.7%.
[0057] S3. Under a nitrogen atmosphere, acetic anhydride (129 mL, 1404 mmol) was added to a reaction flask, and triethylamine (192 mL, 1404 mmol) was slowly added at 0 °C, followed by the addition of intermediate 2 (35.9 g, 117 mmol). After stirring at room temperature for 5 h, the mixture was raised to 90 °C and further heated for 12 h. The reaction mixture was then cooled to 0 °C and extracted with ethyl acetate (3 x 150 mL). The organic layer was washed with a brine solution, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 33.6 g of intermediate 3 at a yield of 87.6%.
[0058] S4. Under a nitrogen atmosphere, intermediate 3 (10 g, 30.4 mmol) was dissolved in completely deoxygenated water (200 mL), and sodium hydroxide (18.2 g, 456 mmol) was added. The mixture was stirred at 90 °C for 0.5 h. The reaction solution was then cooled to <5 °C, and 30 mL of an aqueous citric acid solution (0.5 N) was added dropwise while maintaining the reaction temperature at <5 °C. Then, NaCl (30 g) was added, and the reaction solution was cooled to 0 °C and stirred for 1 h. The greenish-yellow solid product was collected by suction filtration, washed with 30 mL of an aqueous citric acid solution (0.5 N) and pure water, and dried under vacuum to obtain 6.6 g of the product, i.e., 5-bromo-4-chloro-1H-indol-3-ol, at a yield of 88.7%.
[0059] Example 4
[0060] The present example provides a method of preparing 5-bromo-4-chloro-1H-indol-3-ol, comprising the steps of,
[0061] S1. In a reaction flask was added 2-chloro-6-fluorobenzoic acid (14.9 g, 85.4 mmol), 70 mL trifluoromethanesulfonic acid solution, NBS (18.5 g, 98.2 mmol) was added to the above solution in 5 minutes, then iron powder (478 mg, 8.5 mmol) was added, stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was diluted with water and extracted with 50 mL n-hexane for 3 times, the combined extract was washed with 50 mL aqueous sodium thiosulfate solution (5%), dried over magnesium sulfate, concentrated under reduced pressure to obtain 16.2 g of intermediate 1, with a yield of 75.6%;
[0062] S2. In a reaction flask was added 100 mL of tetrahydrofuran at room temperature, intermediate 1 (10 g, 39.6 mmol), pyridine (15.7 g, 198 mmol), glycine (3.6 g, 47.5 mmol), the mixture was stirred, then the temperature was raised to 60°C for 6 h, then the reaction solvent was distilled off, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) and concentrated under reduced pressure to obtain 10.9 g of intermediate 2, with a yield of 90.8%;
[0063] S3. Under a nitrogen atmosphere, acetic anhydride (110 mL, 1200 mmol) was added to a reaction flask, pyridine (100 mL, 1242 mmol) was slowly added at 0°C, intermediate 2 (35.9 g, 117 mmol) was added, stirred at room temperature for 5 h, then the temperature was raised to 80°C, and the reaction was further heated for 16 h. Then the reaction was cooled to 0°C, extracted with ethyl acetate (3x150 mL). The organic layer was washed with a brine solution, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 35.2 g of intermediate 3, with a yield of 91.6%;
[0064] S4. Under a nitrogen atmosphere, intermediate 3 (10 g, 30.4 mmol) was dissolved in completely deoxygenated water (200 mL), then potassium hydroxide (22.5 g, 401 mmol) was added, stirred at 85°C for 1 h. The reaction solution was cooled to <5°C, then 30 mL of aqueous citric acid solution (0.5N) was added dropwise, keeping the reaction temperature at <5°C. Then NaCl (30 g) was added, the reaction solution was cooled to 0°C, and stirred for 1 h. The green-yellow solid product was collected by suction filtration, washed with 30 mL of aqueous citric acid solution (0.5N) and pure water, and dried under vacuum to obtain 6.9 g of product, 5-bromo-4-chloro-1H-indol-3-ol, with a yield of 92.9%.
[0065] Example 5
[0066] This example provides a method for preparing 5-bromo-4-chloro-1H-indol-3-ol, which is basically the same as Example 1, except for the following steps:
[0067] S1. In a reaction flask was added 2-chloro-6-fluorobenzoic acid (14.9 g, 85.4 mmol) in 70 mL of glacial acetic acid and bromine (5.0 mL, 98.2 mmol) was added dropwise over 5 minutes. Iron bromide (2.5 g, 8.5 mmol) was added and stirred at 40 °C for 18 h. After the reaction was completed, the reaction was diluted with water and extracted with 50 mL of n-hexane three times. The combined extracts were washed with 50 mL of sodium thiosulfate aqueous solution (5%) and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain 17.3 g of intermediate 1 at a yield of 80.6%.
[0068] Example 6
[0069] This example provides a method for preparing 5-bromo-4-chloro-1H-indol-3-ol, which is substantially the same as Example 1, except for the following steps:
[0070] S1. In a reaction flask was added 2-chloro-6-fluorobenzoic acid (14.9 g, 85.4 mmol) in 70 mL of glacial acetic acid and bromine (5.0 mL, 98.2 mmol) was added dropwise over 5 minutes. Palladium acetate (0.96 g, 4.3 mmol) was added and stirred at room temperature for 12 h. After the reaction was completed, the reaction was diluted with water and extracted with 50 mL of n-hexane three times. The combined extracts were washed with 50 mL of sodium thiosulfate aqueous solution (5%) and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain 18.6 g of intermediate 1 at a yield of 85.8%.
[0071] Example 7
[0072] This example provides a method for preparing 5-bromo-4-chloro-1H-indol-3-ol, which is substantially the same as Example 1, except for the following steps:
[0073] S1. In a reaction flask was added 2-chloro-6-fluorobenzoic acid (14.9 g, 85.4 mmol) in 70 mL of glacial acetic acid and bromine (5.0 mL, 98.2 mmol) was added dropwise over 5 minutes. Palladium acetate (1.9 g, 8.54 mmol) was added and stirred at room temperature for 15 h. After the reaction was completed, the reaction was diluted with water and extracted with 50 mL of n-hexane three times. The combined extracts were washed with 50 mL of sodium thiosulfate aqueous solution (5%) and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain 19.2 g of intermediate 1 at a yield of 88.9%.
[0074] Comparative Example 1
[0075] This comparative example provides a method for preparing 5-bromo-4-chloro-1H- indol-3-ol which is substantially the same as Example 1 except that in Step S1, no catalyst iron powder is added, and finally 9.2 g of intermediate 1 is obtained by vacuum concentration with a yield of 42.8%.
[0076] Comparative Example 2
[0077] This comparative example provides a method for preparing 5-bromo-4-chloro-1H- indol-3-ol which is substantially the same as Example 1 except that in Step S1, copper bromide is added as catalyst, and finally 9.6 g of intermediate 1 is obtained by vacuum concentration with a yield of 44.6%.
[0078] Comparative Example 3
[0079] This comparative example provides a method for preparing 5-bromo-4-chloro-1H- indol-3-ol which is substantially the same as Example 1 except that in Step S1, bromine (13.5 g, 85.4 mmol) and iron powder (191 mg, 3.4 mmol) are added, and finally 13.1 g of intermediate 1 is obtained by vacuum concentration with a yield of 61.2%.
[0080] Comparative Example 4
[0081] This comparative example provides a method for preparing 5-bromo-4-chloro-1H- indol-3-ol which is substantially the same as Example 1 except that in Step S1, bromine (20.3 g, 128.1 mmol) and iron powder (1434 mg, 25.6 mmol) are added, and finally 14.6 g of intermediate 1 is obtained by vacuum concentration with a yield of 68.1%.
[0082] Comparative Example 5
[0083] This comparative example provides a method for preparing 5-bromo-4-chloro-1H- indol-3-ol which is substantially the same as Example 1 except that in Step S2, triethylamine (14 mL, 99 mmol) and glycine (3 g, 39.6 mmol) are added, and finally 8.7 g of intermediate 2 is obtained by vacuum concentration after column chromatography purification (petroleum ether: ethyl acetate = 3:1) with a yield of 72.1%.
[0084] Comparative Example 6
[0085] This comparative example provides a method for preparing 5-bromo-4-chloro-1H- indol-3-ol which is substantially the same as Example 1 except that in Step S2, triethylamine (44 mL, 316.8 mmol) and glycine (4.8 g, 63.4 mmol) are added, and finally 9.8 g of intermediate 2 is obtained by vacuum concentration after column chromatography purification (petroleum ether: ethyl acetate = 3:1) with a yield of 81.3%.
[0086] The applicant declares that the present application is illustrated by the above-mentioned examples for the preparation of 5-bromo-4-chloro-1H-indol-3-ol, but the present application is not limited to the above-mentioned examples, i.e. it does not mean that the present application must rely on the above-mentioned examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific modes, etc. all fall within the protection scope and disclosure scope of the present application.
[0087] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details in the above-mentioned embodiments, and within the technical concept scope of the present application, various simple modifications can be made to the technical solutions of the present application, and these simple modifications all belong to the protection scope of the present application.
[0088] In addition, it should be noted that each specific technical feature described in the above-mentioned specific embodiments can be combined in any appropriate manner without contradiction, and in order to avoid unnecessary repetition, the present application will not further describe various possible combination manners.
Claims
1. A method for preparing 5-bromo-4-chloro-1H-indole-3-ol, characterized in that, Includes the following steps: S1,2-chloro-6-fluorobenzoic acid undergoes a bromination reaction with a brominating agent under the action of a catalyst to give intermediate 1; S2. Intermediate 1, glycine undergoes an ammoniation reaction under the action of an organic base to obtain intermediate 2; S3. Under an inert gas atmosphere, intermediate 2 and acetic anhydride undergo a cyclization reaction in the presence of an organic base to yield intermediate 3; S4. Under an inert gas atmosphere, intermediate 3 undergoes a hydrolysis reaction under alkaline conditions to obtain the 5-bromo-4-chloro-1H-indole-3-ol; The reaction route is as follows:
2. The preparation method according to claim 1, characterized in that, In step S1, the molar ratio of 2-chloro-6-fluorobenzoic acid, brominating agent, and catalyst is 1:(1-1.3):(0.05-0.2). Preferably, the brominating agent includes one of liquid bromine and NBS.
3. The preparation method according to claim 1, characterized in that, In step S1, the bromination reaction is carried out at a temperature of 25-50°C for 12-24 hours. Preferably, the bromination reaction also requires the addition of a solvent, which includes one of glacial acetic acid and trifluoromethanesulfonic acid; More preferably, the molar ratio of 2-chloro-6-fluorobenzoic acid to solvent is 1:(12-15).
4. The preparation method according to claim 1, characterized in that, In step S1, the catalyst includes one of iron, ferric bromide, and palladium acetate; Preferably, palladium acetate is used as the catalyst, and the reaction needs to be carried out in an inert gas atmosphere.
5. The preparation method according to claim 1, characterized in that, In step S2, the molar ratio of intermediate 1, glycine, and organic base is 1:(1.1-1.5):(3-7); Preferably, the amination reaction is carried out at a temperature of 50-70°C for 4-8 hours.
6. The preparation method according to claim 1, characterized in that, In step S2, the organic base includes one of triethylamine and pyridine; Preferably, the amination reaction also requires the addition of a solvent, which includes one of 1,4-dioxane, tetrahydrofuran, and DMF.
7. The preparation method according to claim 1, characterized in that, In step S3, the molar ratio of intermediate 2, acetic anhydride, and organic base is 1:(9-12):(8-12); Preferably, the cyclization reaction is carried out at a temperature of 70-90°C for 12-16 hours.
8. The preparation method according to claim 1, characterized in that, In step S3, the organic base includes one of trimethylamine, triethylamine, and pyridine.
9. The preparation method according to claim 1, characterized in that, In step S4, the molar ratio of intermediate 3 to alkali is 1:(12-15).
10. The preparation method according to claim 1, characterized in that, In step S4, the hydrolysis reaction is carried out at a temperature of 80-90℃ for a time of 0.5-1.5h. Preferably, the alkali includes one of sodium hydroxide and potassium hydroxide.