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Method for preparing benzocyclobutane compound and derivative thereof

A technology of benzocyclobutane and derivatives is applied in the field of preparation of benzocyclobutane compounds, and can solve the problems of harsh reaction conditions, low synthesis efficiency and high cost of synthesis methods

Inactive Publication Date: 2012-08-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome the disadvantages of existing benzocyclobutane compound synthesis methods, such as high cost, low synthesis efficiency, long synthesis route and harsh reaction conditions, which are not conducive to industrial production, and provide a new A method for preparing benzocyclobutane compounds, the method has cheap and easy-to-obtain raw materials, short reaction steps, high synthesis efficiency, mild synthesis conditions and is conducive to industrial production

Method used

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  • Method for preparing benzocyclobutane compound and derivative thereof
  • Method for preparing benzocyclobutane compound and derivative thereof
  • Method for preparing benzocyclobutane compound and derivative thereof

Examples

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Embodiment 1

[0050] Embodiment 1: the preparation of 3,4-dimethoxyphenylpropionyl chloride

[0051] Add 3,4-dimethoxyphenylpropionic acid (4g, 19.2mmol) in the single-neck round bottom flask of 100ml, add dichloromethane 15ml to dissolve, add thionyl chloride (4.2ml, 57.6mmol ), stirred at room temperature for 3 hours, and evaporated the solvent in the reaction solution in vacuo to obtain a brown-red oil.

Embodiment 2

[0052] Embodiment 2: the preparation of 5,6-dimethoxy-1-indanone

[0053] Add 3,4-dimethoxyphenylpropionyl chloride (19.2mmol) to a 100ml single-necked round-bottomed flask, add 30ml of dichloromethane to dissolve, and add AlCl to the reaction flask at room temperature 3 (5.1g, 38.4mmol), stirred at room temperature for 4 hours, after the reaction ended, the reaction solution was poured into ice water and stirred for 1 hour, extracted with dichloromethane (50ml×3 times), the organic layers were combined, and the organic layer was washed with water (50ml×1 times), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain 3.62 g of khaki crystals with a yield of 98%. 1 H-NMR (300MHz, CDCl 3 ): δ7.18(s, 1H), δ6.89(s, 1H), δ3.97(s, 3H), δ3.91(s, 3H), δ3.05(t, 2H), δ2.68 (t, 2H).

Embodiment 3

[0054] Embodiment 3: the preparation of 2-bromo-5,6-dimethyl-indanone

[0055] The raw material 5,6-dimethoxy-1-indanone (3.62g, 18.9mmol), sodium bromide (3.89g, 37.8mmol) was added in a 100ml single-necked round bottom flask, 50ml of methanol was added, and the oil bath was heated to Reflux at 80°C for 8 hours, and the reaction was completed. After the reaction liquid was cooled to room temperature, it was suction filtered and concentrated to obtain 4.82 g of brown-yellow crystals. Yield 94%. 1 H-NMR (300MHz, CDCl 3 ): δ7.23(s, 1H), δ6.85(s, 1H), δ3.98(s, 3H), δ3.92(s, 3H), δ3.78(q, 1H), δ3.36 (q,2H).

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Abstract

The invention discloses a preparation method of a benzocyclobutane compound (V). The preparation method comprises the following step of: performing halogenation, Friedel-Crafts acylation cyclization, ketone alpha-site hydrohalogenation and Favorskii rearrangement on a phenylpropionic acid type derivative as a starting raw material to finally obtain the compound (V). The invention also discloses a method for preparing the benzocyclobutane compounds (VI), (VII) and (VIII) based on ammonolysis and hydrogenation of the benzocyclobutane compound (V). The preparation method has the advantages of cheap and readily available raw materials, mild reaction conditions, convenience in operation, high synthesis efficiency and contribution to industrial production, and a new approach is provided for preparing the benzocyclobutane compound.

Description

Technical field: [0001] The invention relates to a preparation method of a class of benzocyclobutane compounds and a synthetic intermediate benzocyclobutane derivative suitable for the preparation method. The preparation method can be used to prepare the key intermediate 4,5-dimethoxy-1-methylaminomethylbenzocyclobutane of the anti-angina drug ivabradine. Background technique: [0002] Benzocyclobutane compounds are important components of ivabradine, serotonin, and norepinephrine uptake inhibitors. Their synthetic routes have been reported very early. In 1962, Bunnett J.F. et al. reported on JOC Carbocyclic ring closure reaction with benzyne as intermediate (The Journal of Organic Chemistry.1962, 27:3836~3843), that is, aliphatic nitriles, esters, sulfones and ketones with o-halogenated phenyl groups and amino groups Potassium undergoes a ring closure reaction in liquid ammonia, which lays the foundation for the synthesis of benzocyclobutane derivatives in the future. At ...

Claims

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Application Information

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IPC IPC(8): C07C69/74C07C69/757C07C67/10C07C35/04C07C29/136C07C211/42C07C209/50
Inventor 王进欣夏开国赵金会
Owner CHINA PHARM UNIV
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