New benzocyclobutane, preparation method thereof and application thereof

Abstract

The invention relates to new benzocyclobutane, a preparation method thereof and application thereof. The invention provides a new preparation method for (1S)-4, 5-dimethoxy-1-(methyl-amino-methyl)-benzocyclobutane serving as a key intermediate of ivabradine hydrochloride and addition salt thereof, and meanwhile provides a new benzocyclobutane compound which is an intermediate for preparing the (1S)-4, 5-dimethoxy-1-(methyl-amino-methyl)-benzocyclobutane. In addition, the invention also provides a method for preparing the new benzocyclobutane compound, and meanwhile provides a method for splitting an intermediate product during preparing the new benzocyclobutane compound.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new benzocyclobutane, its preparation method and application. [0002] More specifically, the present invention relates to a compound of formula I-1 in a new (S) configuration and a synthesis method thereof. The structural formula of the compound of formula I-1 is as follows: [0003] [0004] The compound of formula I-1 obtained according to the method of the present invention is an important starting material for the compound of synthetic formula I, and the compound of said formula I is an important intermediate of formula II ivabradine hydrochloride: [0005] Background technique [0006] The chemical name of ivabradine hydrochloride is 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl] Methyl}(methyl)-amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride , is a selective and specific If channel blocker developed by Servier, ...

AI Technical Summary

Problems solved by technology

Though this method has improved the yield of resolution, remaining mother liquor after resolution can't be racemized and recycles, and yield has not been further improved, and simultaneously 60% formula IV compound is discarded, and these discarded Compounds are a potential factor affecting environmental pollution, and the last step of reduction needs to use lithium aluminum hydrogen as a reducing agent, and the reaction is carried out under reflux conditions. The reaction cost is high and the safety is poor, which brings certain problems to large-scale industrial production. difficulty

[0019] The above two methods for synthesizing the compound of formula I all use the compound of formula III to generate a racemic compound by reduction method, and then obtain the target product by the method of resolution and the method of subsequent treatment, and the resolution yield of the first method is too low , the yield of the second resolution method has not been further improved, and the tetrahydrogen lithium aluminum hydrogenation method is used, and the entire reaction process has certain restrictions on industrial production

[0020] In view of the low yield and difficulty in industrialization of the existing (1S)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane synthesis method, the present invention provides a preparation process A new preparation method of (1S)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane that is simple, high in yield and low in cost and suitable for industrial production, and provides A new intermediate for the synthesis of (1S)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane

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