Process for preparing key intermediate 2-ethyl-3-p-hydroxybenzoyl-benzofuran of benzbromarone

Abstract

The invention provides a process for preparing a key intermediate 2-ethyl-3-p-hydroxybenzoyl-benzofuran of benzbromarone. The process comprises the following steps of: (1) by taking 2-ethyl-3-p-methoxybenzoyl-benzofuran as a raw material and alkylbenzene as a reaction solvent, reacting the raw material with the reaction solvent in the presence of an acidic catalyst by a certain quantity; (2) after cooling by using ice water, adding a bit of diluted hydrochloric acid and separating out the water layer, performing decompression distillation on the organic layer so as to recover the solvent, and then concentrating the organic layer until the organic layer is dry; (3) adding a diluted basic liquid to the organic layer concentrated liquid obtained in the step (2), separating out the water layer, adding diluted hydrochloric acid to the water layer for adjusting the pH to the range from 1 to 4, and then adding haloalkane for extraction, and slowly distilling the extract until the extract becomes dry, thereby obtaining solid; and (4) performing recrystallization separation on the solid obtained in the step (3) by using petroleum ether, thus obtaining the 2-ethyl-3-p-hydroxybenzoyl-benzofuran of benzbromarone. The yield is over 90% and the liquid phase content is greater than or equal to 98%. The process is easy to control, greatly reduced in cost, and convenient for realizing industrial mass production.

Description

Technical field

[0001] The invention relates to a preparation method of pharmaceutical intermediates, in particular to a preparation process of 2-ethyl-3-p-hydroxybenzoyl-benzofuran, a key intermediate of benzbromarone medicine. Background technique

[0002] Benzbromarone (Benzbromarone) is a uric acid excretion accelerator developed by the French company Labaz. It was launched in Germany in 1971 and is clinically used to accelerate the excretion of uric acid and the treatment of gout. 2-Ethyl-3-p-hydroxybenzoyl-benzofuran is a key intermediate in the synthesis of benzbromarone. The synthetic methods of 2-ethyl-3-p-hydroxybenzoyl-benzofuran that have been published in domestic and foreign literature are all based on 2-ethyl-3-p-methoxybenzoyl-benzofuran as raw material Pyridine hydrochloride is a catalyst for the reaction at 210-220°C. The catalyst pyridine hydrochloride used in the process is easy to absorb moisture, is difficult to prepare and store, and is difficult to purch...

Examples

Embodiment 1

[0019] Add 250ml of xylene, 28g (0.1mol) of 2-ethyl-3-p-methoxybenzoyl-benzofuran, and 40.9g (0.3mol) of zinc chloride into a 500ml four-necked flask and stir at 60℃ for reaction 6 hour. After cooling with ice water, add 150ml of 25% dilute hydrochloric acid to separate the water layer. The organic layer is distilled under reduced pressure to recover the solvent. The organic layer is concentrated to dryness. Add 80ml of 15% sodium hydroxide solution to the concentrated organic layer to separate the water layer. Add 25% dilute hydrochloric acid to the water layer to adjust the pH=3, then add chloroform for extraction, and slowly distill the extract to dryness to obtain a solid, which is recrystallized and separated with petroleum ether to obtain 2-ethyl-3-pair Hydroxybenzoyl-benzofuran. The yield is 90%, and the liquid content is 99%.

Embodiment 2

[0021] Add 250ml of toluene, 28g (0.1mol) of 2-ethyl-3-p-methoxybenzoyl-benzofuran, 48.7g (0.3mol) of ferric chloride in a 500ml four-necked flask and stir at 95℃ for reaction 12 hour. After cooling with ice water, add 150ml of 25% dilute hydrochloric acid to separate the water layer. The organic layer is distilled under reduced pressure to recover the solvent. The organic layer is concentrated to dryness. Add 80ml of 15% sodium hydroxide solution to the concentrated organic layer to separate the water layer and the water layer. Add 25% dilute hydrochloric acid to adjust PH=3, then add chloroform for extraction, and slowly distill the extract to dryness to obtain a solid, which is recrystallized and separated with petroleum ether to obtain 2-ethyl-3-p-hydroxybenzene Formyl-benzofuran. The yield was 91%, and the liquid content was 98%.

Embodiment 3

[0023] Add 250ml of xylene, 28g (0.1mol) of 2-ethyl-3-p-methoxybenzoyl-benzofuran, and 56.9g (0.3mol) of titanium tetrachloride into a 500ml four-necked flask with stirring at 70℃. 6 hours. After cooling with ice water, add 150ml of 25% dilute hydrochloric acid to separate the water layer. The organic layer is distilled under reduced pressure to recover the solvent. The organic layer is concentrated to dryness. Add 80ml of 15% sodium hydroxide solution to the concentrated organic layer to separate the water layer and the water layer. Add 25% dilute hydrochloric acid to adjust the PH=3, then add chloroform for extraction, and slowly distill the extract to dry out to obtain a solid, which is recrystallized with petroleum ether to obtain 2-ethyl-3-p-hydroxyl Benzoyl-benzofuran. The yield is 90%, and the liquid content is 99%.

Technical field

[0001] The invention relates to a preparation method of pharmaceutical intermediates, in particular to a preparation process of 2-ethyl-3-p-hydroxybenzoyl-benzofuran, a key intermediate of benzbromarone medicine. Background technique

[0002] Benzbromarone (Benzbromarone) is a uric acid excretion accelerator developed by the French company Labaz. It was launched in Germany in 1971 and is clinically used to accelerate the excretion of uric acid and the treatment of gout. 2-Ethyl-3-p-hydroxybenzoyl-benzofuran is a key intermediate in the synthesis of benzbromarone. The synthetic methods of 2-ethyl-3-p-hydroxybenzoyl-benzofuran that have been published in domestic and foreign literature are all based on 2-ethyl-3-p-methoxybenzoyl-benzofuran as raw material Pyridine hydrochloride is a catalyst for the reaction at 210-220°C. The catalyst pyridine hydrochloride used in the process is easy to absorb moisture, is difficult to prepare and store, and is difficult to purch...

Examples

Embodiment 1

[0019] Add 250ml of xylene, 28g (0.1mol) of 2-ethyl-3-p-methoxybenzoyl-benzofuran, and 40.9g (0.3mol) of zinc chloride into a 500ml four-necked flask and stir at 60℃ for reaction 6 hour. After cooling with ice water, add 150ml of 25% dilute hydrochloric acid to separate the water layer. The organic layer is distilled under reduced pressure to recover the solvent. The organic layer is concentrated to dryness. Add 80ml of 15% sodium hydroxide solution to the concentrated organic layer to separate the water layer. Add 25% dilute hydrochloric acid to the water layer to adjust the pH=3, then add chloroform for extraction, and slowly distill the extract to dryness to obtain a solid, which is recrystallized and separated with petroleum ether to obtain 2-ethyl-3-pair Hydroxybenzoyl-benzofuran. The yield is 90%, and the liquid content is 99%.

Embodiment 2

[0021] Add 250ml of toluene, 28g (0.1mol) of 2-ethyl-3-p-methoxybenzoyl-benzofuran, 48.7g (0.3mol) of ferric chloride in a 500ml four-necked flask and stir at 95℃ for reaction 12 hour. After cooling with ice water, add 150ml of 25% dilute hydrochloric acid to separate the water layer. The organic layer is distilled under reduced pressure to recover the solvent. The organic layer is concentrated to dryness. Add 80ml of 15% sodium hydroxide solution to the concentrated organic layer to separate the water layer and the water layer. Add 25% dilute hydrochloric acid to adjust PH=3, then add chloroform for extraction, and slowly distill the extract to dryness to obtain a solid, which is recrystallized and separated with petroleum ether to obtain 2-ethyl-3-p-hydroxybenzene Formyl-benzofuran. The yield was 91%, and the liquid content was 98%.

Embodiment 3

[0023] Add 250ml of xylene, 28g (0.1mol) of 2-ethyl-3-p-methoxybenzoyl-benzofuran, and 56.9g (0.3mol) of titanium tetrachloride into a 500ml four-necked flask with stirring at 70℃. 6 hours. After cooling with ice water, add 150ml of 25% dilute hydrochloric acid to separate the water layer. The organic layer is distilled under reduced pressure to recover the solvent. The organic layer is concentrated to dryness. Add 80ml of 15% sodium hydroxide solution to the concentrated organic layer to separate the water layer and the water layer. Add 25% dilute hydrochloric acid to adjust the PH=3, then add chloroform for extraction, and slowly distill the extract to dry out to obtain a solid, which is recrystallized with petroleum ether to obtain 2-ethyl-3-p-hydroxyl Benzoyl-benzofuran. The yield is 90%, and the liquid content is 99%.

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