Preparation method of benzofuran derivative

Abstract

The invention discloses a preparation method for synthesizing a benzofuran derivative. The specific implementation method is as shown in the specification. The method has novel synthetic route, simpleand convenient operation, high yield, and good safety, and is suitable for industrial production. A novel synthetic method of an intermediate VI is also designed, a Wittig reaction is carried out, and then ring-closing is carried out to obtain a benzofuran ring.

Description

technical field

[0001] The invention relates to the technical field of organic compound synthesis, in particular to a preparation method of benzofuran compounds. Background technique

[0002] Benzofuran compounds have a variety of good physiological activities, such as antitumor, antibacterial, and antioxidative effects, and have attracted widespread attention. Benzofuran compounds are important frameworks for the synthesis of natural products and pharmaceuticals. For example, lifitegrast, a new type of small-molecule integration inhibitor, can be used to treat chronic ocular inflammatory diseases, which was approved by the FDA on July 11, 2016.

[0003] The structure of Litahast is shown below:

[0004]

[0005] As an important intermediate of pharmaceutical composition, the synthesis of 6-carboxylic acid benzofuran (compound VII) is difficult. Currently published synthesis methods mainly include the following.

[0006] Patent EP 816348 discloses a preparation method...

Examples

Embodiment 1

[0065] Preparation of 6-carboxylic acid benzofuran

[0066]

[0067] 1. Add compound I (200kg, 1450mol, 1.0eq) and methanesulfonic acid (1000L) into a clean reactor, and stir to mix. Add compound II (305kg, 2170 mol, 1.5eq) in batches to the reaction flask, control the reaction temperature within 80°C, heat at 80°C after the addition, and stir for 3 hours. The starting material was consumed by TLC analysis. The temperature of the reaction solution was lowered to 50° C., 1500 L of pure water was added, and the mixture was stirred at room temperature for 1 hour after adding water. Extract the product with EA:MeOH (10:1) (500L x 6), combine the organic phases, and wash with saturated brine (300L x 2). Anhydrous sodium sulfate (20 kg) was dried and filtered to remove sodium sulfate. The organic phase was extracted with 10% NaOH aqueous solution (300L x 4), and the aqueous phase was combined, and the pH value of the aqueous phase was adjusted to about 3-4 with concentrated hy...

Embodiment 2

[0077]

[0078] Add compound IV to the reaction kettle 2 (8.6kg, 44.41mol, 1.0eq), compound Ⅴ (29.05 kg, 66.61mol, 1.5eq) and THF (80L), nitrogen protection. Cool down to 0°C, add sodium methoxide (3.97kg, 73.61mol, 1.65eq) THF solution (1M) dropwise to the reactor, control the temperature at 0-5°C, stir for 30min, continue to dropwise add sodium methoxide ( 1.30kg, 24.06mol, 0.54eq) THF solution (1M), temperature controlled at 0-5°C, stirred for 1 hour. According to TLC analysis, the consumption of raw materials was complete, and 200 L of petroleum ether was added to the reaction solution to quench the reaction. Then add 200L of petroleum ether, and filter the insoluble matter. Concentrate to obtain an oily liquid, disperse it with 200 L of petroleum ether, and filter the reaction liquid. The filter cake was beaten with petroleum ether (200L x 2), and the organic phases were combined and concentrated to dryness. Continue to disperse 50L with petroleum ether, filter to ...

Embodiment 3

[0080]

[0081] Add compound IV to the reaction kettle 3 (9.41kg, 44.41mol, 1.0eq), compound Ⅴ (29.05kg, 66.61mol, 1.5eq) and THF (80L), nitrogen protection. Cool down to 0°C, dropwise add a THF solution (1M) of potassium tert-butoxide (8.26kg, 73.61mol, 1.65eq) into the reaction kettle, control the temperature at 0-5°C, stir for 30min, continue to add tert-butoxide dropwise into the reaction kettle Potassium butoxide (2.70kg, 24.06mol, 0.54eq) THF solution (1M) was stirred at a temperature of 0-5°C for 1 hour. According to TLC analysis, the consumption of raw materials was complete, and 200 L of petroleum ether was added to the reaction solution to quench the reaction. Then add 200L petroleum ether, and filter the insoluble matter. Concentrate to obtain an oily liquid, disperse it with 200 L of petroleum ether, and filter the reaction liquid. The filter cake was beaten with petroleum ether (200L x 2), and the organic phases were combined and concentrated to dryness. Co...

technical field

[0001] The invention relates to the technical field of organic compound synthesis, in particular to a preparation method of benzofuran compounds. Background technique

[0002] Benzofuran compounds have a variety of good physiological activities, such as antitumor, antibacterial, and antioxidative effects, and have attracted widespread attention. Benzofuran compounds are important frameworks for the synthesis of natural products and pharmaceuticals. For example, lifitegrast, a new type of small-molecule integration inhibitor, can be used to treat chronic ocular inflammatory diseases, which was approved by the FDA on July 11, 2016.

[0003] The structure of Litahast is shown below:

[0004]

[0005] As an important intermediate of pharmaceutical composition, the synthesis of 6-carboxylic acid benzofuran (compound VII) is difficult. Currently published synthesis methods mainly include the following.

[0006] Patent EP 816348 discloses a preparation method...

Examples

Embodiment 1

[0065] Preparation of 6-carboxylic acid benzofuran

[0066]

[0067] 1. Add compound I (200kg, 1450mol, 1.0eq) and methanesulfonic acid (1000L) into a clean reactor, and stir to mix. Add compound II (305kg, 2170 mol, 1.5eq) in batches to the reaction flask, control the reaction temperature within 80°C, heat at 80°C after the addition, and stir for 3 hours. The starting material was consumed by TLC analysis. The temperature of the reaction solution was lowered to 50° C., 1500 L of pure water was added, and the mixture was stirred at room temperature for 1 hour after adding water. Extract the product with EA:MeOH (10:1) (500L x 6), combine the organic phases, and wash with saturated brine (300L x 2). Anhydrous sodium sulfate (20 kg) was dried and filtered to remove sodium sulfate. The organic phase was extracted with 10% NaOH aqueous solution (300L x 4), and the aqueous phase was combined, and the pH value of the aqueous phase was adjusted to about 3-4 with concentrated hy...

Embodiment 2

[0077]

[0078] Add compound IV to the reaction kettle 2 (8.6kg, 44.41mol, 1.0eq), compound Ⅴ (29.05 kg, 66.61mol, 1.5eq) and THF (80L), nitrogen protection. Cool down to 0°C, add sodium methoxide (3.97kg, 73.61mol, 1.65eq) THF solution (1M) dropwise to the reactor, control the temperature at 0-5°C, stir for 30min, continue to dropwise add sodium methoxide ( 1.30kg, 24.06mol, 0.54eq) THF solution (1M), temperature controlled at 0-5°C, stirred for 1 hour. According to TLC analysis, the consumption of raw materials was complete, and 200 L of petroleum ether was added to the reaction solution to quench the reaction. Then add 200L of petroleum ether, and filter the insoluble matter. Concentrate to obtain an oily liquid, disperse it with 200 L of petroleum ether, and filter the reaction liquid. The filter cake was beaten with petroleum ether (200L x 2), and the organic phases were combined and concentrated to dryness. Continue to disperse 50L with petroleum ether, filter to ...

Embodiment 3

[0080]

[0081] Add compound IV to the reaction kettle 3 (9.41kg, 44.41mol, 1.0eq), compound Ⅴ (29.05kg, 66.61mol, 1.5eq) and THF (80L), nitrogen protection. Cool down to 0°C, dropwise add a THF solution (1M) of potassium tert-butoxide (8.26kg, 73.61mol, 1.65eq) into the reaction kettle, control the temperature at 0-5°C, stir for 30min, continue to add tert-butoxide dropwise into the reaction kettle Potassium butoxide (2.70kg, 24.06mol, 0.54eq) THF solution (1M) was stirred at a temperature of 0-5°C for 1 hour. According to TLC analysis, the consumption of raw materials was complete, and 200 L of petroleum ether was added to the reaction solution to quench the reaction. Then add 200L petroleum ether, and filter the insoluble matter. Concentrate to obtain an oily liquid, disperse it with 200 L of petroleum ether, and filter the reaction liquid. The filter cake was beaten with petroleum ether (200L x 2), and the organic phases were combined and concentrated to dryness. Co...

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