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2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran and application thereof

A technology of propoxybenzoyl group and benzoyl group is applied in the field of key intermediates for synthesizing dronedarone, which can solve the problems of being unsuitable for industrialized mass preparation and high preparation cost, avoiding the use of metal catalysts, reducing Preparation cost, avoid the effect of high pressure hydrogenation operation

Active Publication Date: 2011-05-25
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Among them, 2-n-butyl-3-(4-(3-di-n-butylaminopropoxy)benzoyl)-5-aminobenzofuran is used as a key intermediate for preparing dronedarone, and its synthesis process Among them, expensive metal catalysts are required, and high-pressure hydrogenation operation is required, the preparation cost is high, and it is not suitable for industrial mass preparation

Method used

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  • 2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran and application thereof
  • 2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran and application thereof
  • 2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Preparation of 2-n-butyl-3-(4-(3-chloropropoxy)benzoyl)-5-acetamidobenzofuran (II-1)

[0071] Dissolve 2-n-butyl-5-acetylaminobenzofuran (0.02mol, 4.63g) in 40ml of dichloromethane, add 4-(3-chloropropoxy)-benzoyl chloride (0.02mol, 4.77g ), stirred for 10 minutes, cooled to 2±2°C in an ice-water bath, added anhydrous aluminum trichloride (0.044mol, 5.87g) in batches, and stirred at room temperature for 2 hours. According to the post-processing operation in General Method 1, the target compound II-1 was obtained, 6.31 g of white solid, and the yield was 73.7%.

[0072] ESI-MS[M+H] + :428.18

[0073] 1 H-NMR (CDCl 3 ): δ0.86(t, 3H, J=7.2Hz), 1.30-1.36(m, 2H), 1.68-1.76(m, 2H), 2.10(s, 3H), 2.25-2.30(m, 2H), 2.86(t, 2H, J=7.2Hz), 3.75(t, 2H, J=6.0Hz), 4.20(t, 2H, J=5.6Hz), 6.94(d, 2H, J=8.8Hz), 7.31( s, 1H), 7.33 (s, 1H, D 2 O exchange disappeared), 7.38 (d, 1H, J = 8.4Hz), 7.55 (d, 1H, J = 8.4Hz), 7.82 (d, 2H, J = 8.8Hz).

Embodiment 2

[0075] Preparation of 2-n-butyl-3-(4-(3-bromopropoxy)benzoyl)-5-acetamidobenzofuran (II-2)

[0076] Dissolve 2-n-butyl-5-acetylaminobenzofuran (0.02mol, 4.63g) in 40ml of dichloromethane, add 4-(3-bromopropoxy)-benzoyl chloride (0.02mol, 5.55g ), and stirred for 10 minutes. Cool down to 2±2°C in an ice-water bath, add anhydrous aluminum trichloride (0.044mol, 5.87g) in batches, control the temperature below 10°C and stir for reaction for 3 hours. According to the post-treatment operation in General Method 1, the target compound II-2 was obtained, 7.04 g of white solid, with a yield of 74.5%.

[0077] ESI-MS[M+H] + : 472.10

[0078] 1 H-NMR (CDCl 3 ): δ0.85(t, 3H, J=7.2Hz), 1.30-1.35(m, 2H), 1.65-1.76(m, 2H), 2.09(s, 3H), 2.14-2.25(m, 2H), 2.84(t, 2H, J=7.2Hz), 3.57(t, 2H, J=5.6Hz), 4.21(t, 2H, J=5.6Hz), 6.95(d, 2H, J=8.8Hz), 7.30( s, 1H), 7.35 (s, 1H, D 2 O exchange disappeared), 7.39 (d, 1H, J = 8.4Hz), 7.57 (d, 1H, J = 8.4Hz), 7.83 (d, 2H, J = 8.8Hz).

Embodiment 3

[0080] Preparation of 2-n-butyl-3-(4-(3-chloropropoxy)benzoyl)-5-propionylaminobenzofuran (II-3)

[0081]Dissolve 2-n-butyl-5-propionylaminobenzofuran (0.02mol, 4.91g) in 40ml of dichloromethane, add 4-(3-chloropropoxy)-benzoyl chloride (0.02mol, 4.77 g), stirring for 10 minutes, cooling down to 2±2°C in an ice-water bath, adding anhydrous aluminum trichloride (0.044mol, 5.87g) in batches, and stirring at room temperature for 2 hours. According to the post-processing operation in General Method 1, the target compound II-3 was obtained, 6.43 g of white solid, and the yield was 72.7%.

[0082] ESI-MS[M+H] + :442.17

[0083] 1 H-NMR (CDCl 3 ): δ0.82-0.90(t, 3H, J=7.2Hz), 1.05(t, 3H, J=7.6Hz), 1.31-1.36(m, 2H), 1.64-1.77(m, 2H), 2.12( q, 2H, J=7.6Hz), 2.15-2.27(m, 2H), 2.83(t, 2H, J=7.2Hz), 3.77(t, 2H, J=5.6Hz), 4.19(t, 2H, J =5.6Hz), 6.94(d, 2H, J=8.8Hz), 7.31(s, 1H), 7.38(d, 1H, J=8.4Hz), 7.49(s, 1H, D 2 O exchange disappeared), 7.57 (d, 1H, J = 8.4 Hz), 7.82 (d, 2H, J = ...

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Abstract

The invention discloses 2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran and application thereof. The 2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran can be used for preparing dronedarone and pharmaceutically acceptable salts of the dronedarone. The 2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran has the characteristics that raw material is available, reaction conditions are mild, and operation is convenient, and the use of an expensive metal catalyst and a high-pressure hydrogenation operation are avoided; dronedarone hydrochloride is obtained from an intermediate (III) by the hydrolysis reaction, the salification, the purification, the sulfonylation, the salification and the purification. The purities of intermediates and target products in various steps are high, and the qualities are stable and controllable, and the preparation cost of the dronedarone is greatly reduced; and the 2-n-butyl-3-(4-subsitituted propylbenzoyl)-5-substituted amino benzofuran is suitable for a large amount of industrialization preparations. The general structure formula of the compound (I) is shown in the specification.

Description

technical field [0001] The invention relates to a kind of key intermediate for synthesizing dronedarone: 2-n-butyl-3-(4-substituted propoxybenzoyl)-5-substituted aminobenzofuran. Background technique [0002] Dronedarone hydrochloride (dronedarone), the chemical name is N-(2-n-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuryl ) Methanesulfonamide hydrochloride, developed by Sanofi-Aventis of France, can effectively reduce atrial fibrillation or atrial flutter, is an antiarrhythmic drug, suitable for patients with paroxysmal or persistent atrial fibrillation or patients with atrial flutter. In July 2009, it was approved for marketing by the US Food and Drug Administration (FDA). [0003] [0004] Dronedarone hydrochloride (dronedaone) [0005] Atrial fibrillation is a very complex disease that can increase the risk of stroke by 5 times, worsen the prognosis of patients with cardiovascular risk factors, and increase the mortality rate by two times. Atrial flutte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/80
Inventor 李建其王冠张飞龙
Owner SHANGHAI INST OF PHARMA IND CO LTD
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