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Synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane

A methylaminomethyl, benzocyclobutane technology, applied in the preparation of aminohydroxy compounds, chemical instruments and methods, preparation of organic compounds, etc., can solve the problem of low total reaction yield, high production cost, and unsuitable industrialization. production and other issues

Active Publication Date: 2010-10-13
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The disadvantage of this method is that the total reaction yield is low, only 2-3%, so the production cost of this method is high, and it is not suitable for industrial production

Method used

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  • Synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane
  • Synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane
  • Synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane

Examples

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example 1

[0035] Example 1 4, the preparation of 5-dimethoxybenzocyclobutane-1-carboxylic acid

[0036] 120 g of 1-cyano-4,5-dimethoxybenzocyclobutane, 300 ml of methanol, and 300 ml of water were added to a 1000 ml reaction flask, and 36 g of sodium hydroxide was added with stirring. Raise the temperature to 80°C and react for 4 hours, TCL detects that the reaction is complete, drop the temperature at 20-25°C and add about 150ml of hydrochloric acid to pH<1, stir and crystallize for two hours, filter, dry at 50-55°C for 8 hours, dry weight 127g, mp: 142.5-143°C, yield 93%.

example 2

[0037] Example 2 Preparation of 4,5-dimethoxybenzocyclobutyl-1-methanol

[0038] Add 31.2g of 4,5-dimethoxybenzocyclobutane-1-carboxylic acid and 300ml of tetrahydrofuran to a dry 1000ml reaction flask, lower the temperature, add 21g of sodium borohydride at t<0°C, and dropwise add 25.8g of sulfuric acid , keep warm for 10nm, stir naturally for 1 hour, reflux for 30min, drop the temperature at t<0°C and add 180ml of methanol dropwise. After the dropwise addition, reflux for 30nm, evaporate to dryness under reduced pressure, add 200ml of dichloromethane and 500ml of water, separate layers, extract the water layer with 100ml of dichloromethane, wash the organic layer with 300ml of water, combine the organic layers, and reduce the pressure below 50°C The organic layer was evaporated to dryness to obtain 29.4 g of an oily substance.

example 3

[0039] Example 3 Preparation of 4,5-dimethoxybenzocyclobutyl-1-methylsulfonate

[0040] Add 29.4g of 4,5-dimethoxybenzocyclobutyl-1-methanol to 100ml of dichloromethane to dissolve, add 10ml of pyridine and dropwise add 25.4g of methanesulfonyl chloride at t<0°C, after the addition is completed, 8-12 Incubate at ℃ for 6-8 hours, TCL detection (chloroform:methanol=3:1), t<20 ℃, add 10% sulfuric acid to wash the organic layer to PH<2, let stand to separate the layers, extract the water layer with 100ml dichloromethane, organic The layers were washed with 300 ml of water, and the organic layers were combined. The organic layer was evaporated to dryness under reduced pressure below 50°C, and 100ml of isopropanol was added to crystallize. Filter, dry at 50-55°C for 8 hours, dry weight 36.7g, mp: 97-98°C, yield 90%.

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Abstract

The invention provides a synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane, which is an important intermediate of Ivabradine. The method comprises the following steps of: carrying out hydrolyzing, reducing, sulfonylation or halogenation reaction, alkylation and deprotection on 1-cyano-4,5-Dimethoxy-1-cyanobenzocyclobutane used as a raw material to obtain 4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane, and finally splitting with right-hand mandelic acid to obtain the (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane. The method has the advantages of high yield, high purity of chemical and enantiomer (more than 99.5 percent), low cost and suitability for industrial production.

Description

technical field [0001] The invention provides a method for synthesizing an important intermediate (1S)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane of ivabradine, which belongs to the field of medicine and chemical industry . Background technique [0002] The preparation of ivabradine and its addition salts with pharmaceutically acceptable acids, especially its hydrochloride, is described in European patent specification EP0534859, which describes the synthesis of compounds of formula (I) : take the racemic nitrile of formula (II) as raw material, borane reduction, add hydrochloric acid to obtain the hydrochloride of racemic amine of formula (Ⅲ), then convert to carbamate of formula (Ⅳ), and then reduce to formula (Ⅴ) methylated amine, and finally use camphorsulfonic acid to resolve the compound of formula (Ⅴ), thereby generating the compound of formula (I). [0003] [0004] The disadvantage of this method is that the total reaction yield is low, only 2-3%, so ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/74C07C213/10C07C213/00
CPCY02P20/55
Inventor 陈为人刘雄
Owner ZHEJIANG MENOVO PHARMA
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