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Preparation method of (1S)-4,5-dimethoxy-1-((methyl amino) methyl) benzo cyclobutane

A technology of benzocyclobutane and dimethoxy, applied in the field of preparation of -4,5-dimethoxy-1-[methyl] benzocyclobutane, can solve the problem of increasing isomer content , high production cost and other issues, to achieve the effect of low cost, mild reaction conditions and high yield

Active Publication Date: 2014-01-08
江苏宇田医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main disadvantage of this method is racemization during the reaction with methylamine, resulting in an increase in the content of isomers, and sodium borohydride and iodine are used as reducing agents in the final carbonyl reduction reaction, and the production cost is relatively high

Method used

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  • Preparation method of (1S)-4,5-dimethoxy-1-((methyl amino) methyl) benzo cyclobutane
  • Preparation method of (1S)-4,5-dimethoxy-1-((methyl amino) methyl) benzo cyclobutane
  • Preparation method of (1S)-4,5-dimethoxy-1-((methyl amino) methyl) benzo cyclobutane

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Effect test

Embodiment 1

[0039] Example 1, a preparation method of (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane, the steps are as follows:

[0040] (1) Reaction of compound (1S)-4,5-dimethoxy-1-(aminomethyl)benzocyclobutane represented by formula I-1 with orthoformate reagents to prepare formula I-2 The compound (1S)-4,5-dimethoxy group-1-alkoxymethyliminomethyl benzocyclobutane, the molar ratio of the compound represented by formula I-1 and the orthoformate reagent is 1:1.5 ;In I-2: R is C 1 -C 2 alkyl;

[0041] (2) The compound represented by formula I-2 is reduced with borohydride in an appropriate amount of alcohol solvent to obtain the target compound (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzene And cyclobutane; The molar ratio of the compound represented by formula I-2 and borohydride is 1:0.5.

Embodiment 2

[0042] Embodiment 2, a preparation method of (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane, the steps are as follows:

[0043] (1) Reaction of compound (1S)-4,5-dimethoxy-1-(aminomethyl)benzocyclobutane represented by formula I-1 with orthoformate reagents to prepare formula I-2 The compound (1S)-4,5-dimethoxy group-1-alkoxymethyliminomethyl benzocyclobutane, the mol ratio of the compound represented by formula I-1 and the orthoformate reagent is 1: 10 ;In I-2: R is C 1-C 2 alkyl;

[0044] (2) The compound represented by formula I-2 is reduced with borohydride in an appropriate amount of alcohol solvent to obtain the target compound (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzene And cyclobutane; The molar ratio of the compound represented by formula I-2 and borohydride is 1: 1.5.

Embodiment 3

[0045] Example 3, the preparation method of (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane, the steps are as follows:

[0046] In a 250 mL three-necked reaction flask, add (1S)-4,5-dimethoxy-1-aminomethylbenzocyclobutane 38.7 g (0.2 mol), 220 mL (2.0 mol) trimethyl orthoformate , stirred and refluxed for 10 h, TLC showed that the reaction of the raw materials was complete, and the solvent was evaporated to dryness under reduced pressure to obtain 56.9 g of brown oil, which was directly put into the next reaction without purification.

[0047] In a 250 mL reaction bottle, add the above step material, 150 mL of absolute ethanol, cool in an ice-water bath to below 0°C, add a total of 7.5 g of sodium borohydride in portions under stirring, heat up to room temperature and react for 20 minutes, and then heat up to Reflux reaction, about 3 h reaction is complete. Evaporate the solvent under reduced pressure, add 150 mL of dichloromethane to the residue to dissolve, wash ...

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Abstract

The invention relates to a preparation method of (1S)-4,5-dimethoxy-1-((methyl amino) methyl) benzo cyclobutane. The preparation method is characterized in that a compound (1S)-4,5-dimethoxyl-1-(amino methyl) benzo cyclobutane benzo cyclobutane shown as a formula I-1 reacts with ortho-formate reagent to obtain a compound (1S)-4,5-dimethoxyl-1-alcoxyl methylenimine methyl benzo cyclobutane shown as a formula I-2, the compound shown as the formula I-2 is reduced with hydroboron in right amount of alcohol solvent, so as to obtain the target compound (1S)-4,5-dimethoxyl-1-((methyl amino) methyl) benzo cyclobutane. The preparation method provided by the invention is simple, reaction condition is mild, and raw materials are clean and available, thus being applicable to industrial amplification production.

Description

technical field [0001] The invention relates to a method for synthesizing an important intermediate of ivabradine hydrochloride, in particular to (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane preparation. Background technique [0002] Ivabradine hydrochloride (Ivabradine hydrochlorid), chemical name: 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-triene -7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepine-2-one hydrochloride , is the first selective and specific cardiac pacing current inhibitor developed by Servier, France. Treatment of chronic stable angina with normal sinus rhythm and contraindication or intolerance to beta-blockers. [0003] The chemical structural formula of ivabradine hydrochloride is as follows formula II: [0004] [0005] II [0006] About the synthesis of ivabradine hydrochloride, the current literature reports mainly contain the following several methods: [0007] 1. In the US patent document U...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/74C07C213/08
Inventor 朱万里
Owner 江苏宇田医药有限公司
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