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Method for synthesizing (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane

A carbonylaminomethyl, benzocyclobutane technology, applied in the field of pharmaceutical synthesis, can solve the problems of high production cost, unsuitable for industrialized production, low total yield and the like, and achieves good product quality, easy recovery and application, and elimination. The effect of less spin pollution

Active Publication Date: 2018-12-07
安徽美诺华药物化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The total reaction yield of the above method is extremely low, only 2-3%, and the production cost is high, so it is not suitable for industrialized production
[0005] And for ivabradine key intermediate (1S)-4, the preparation method of 5-dimethoxy-1-(carbonylaminomethyl) benzocyclobutane has not been reported in the prior art

Method used

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  • Method for synthesizing (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane
  • Method for synthesizing (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane
  • Method for synthesizing (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane

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preparation example Construction

[0030] The synthesis method of (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane in this embodiment includes the following steps:

[0031] (1) Put 500mL dichloromethane, 10mL absolute ethanol, 100g compound of formula 5 into the reaction flask, stir and slowly raise the temperature to 35℃, add 35g S-(-)-phenethylamine dropwise at 35℃, and keep the dripping process Slowly heat, and then continue to heat up and reflux for 30-60 minutes after the addition is completed (solids may be generated during the reflux process, and the stirring speed will be increased immediately);

[0032] After refluxing, cool to 15-20°C and keep stirring for 3 to 5 hours, filter, and wash the filter cake with a mixed solution of 100 mL of dichloromethane and 2 mL of ethanol, and retain the mother liquor;

[0033] Dry under reduced pressure at 40~45℃ for 8 hours, check the chiral purity by Chiral HPLC ≥97%, the dry weight of the collected material is 65.5g, the resolution yield is 41.3%, the compound ...

Embodiment 2

[0041] (1) Put 500mL chloroform, 20mL absolute ethanol, 100g compound of formula 5 into the reaction flask, stir and slowly raise the temperature to 35℃, add 32g S-(-)-phenethylamine dropwise at 35℃, and keep the dripping process Slowly heat, and then continue to heat and reflux for 30-60 minutes after the addition is complete;

[0042] After refluxing, cool to 15~20℃ and keep stirring for 3~5 hours, filter, wash the filter cake with 100mL chloroform, and keep the mother liquor;

[0043] Dry under reduced pressure at 40-45°C for 8 hours, check chiral purity by Chiral HPLC ≥97%, the dry weight of the collected material is 72.8g, and the resolution yield is 46%.

[0044] (2) Add the separated mother liquor to a 1000mL reaction flask, adjust the pH to less than 4 with 6N hydrochloric acid, stand still for layering to obtain an organic layer, wash the organic layer with 100mL water again, and then stand for layering to obtain an organic layer; concentrate under reduced pressure Obtain o...

Embodiment 3

[0051] (1) Put 500mL 1,2-dichloroethane, 10mL absolute ethanol, 100g compound of formula 5 into the reaction flask, stir and slowly raise the temperature to 35℃, and add 40g S-(-)-phenethylamine dropwise at 35℃ , Keep heating slowly during the dripping process, and keep the temperature at 60℃ for 30-60 minutes after dripping;

[0052] After refluxing, cool to 15-20°C and keep stirring for 3 to 5 hours, filter, and wash the filter cake with a mixed solution of 100 mL 1,2-dichloroethane and 10 mL ethanol, and retain the mother liquor;

[0053] It was dried under reduced pressure at 40-45°C for 8 hours, the chiral purity was detected by Chiral HPLC ≥ 97%, the dry weight of the collected material was 75.9 g (the compound of formula 4), and the resolution yield was 48.1%.

[0054] (2) The resulting separated mother liquor was added to a 1000 mL reaction flask, adjusted to pH less than 2 with 6N hydrochloric acid, left to stand for layering to obtain an organic layer, the organic layer was...

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Abstract

The invention relates to a method for synthesizing (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane. The method provided by the invention does not need complicated high-cost column chromatographic methods for product purification or other special equipment, is good in operability, mild and safe in process, simple in reaction operation and beneficial for industrial production; and halogenated hydrocarbons are used as a solvent and are easy to recover and to use indiscriminately, and S-1-phenylethylamine is used as a resolving agent and is low in price and easy to recover, so production cost is greatly reduced. According to the invention, the synthesis is performed in organic acid, so racemization pollution is low, and environmentally friendliness is achieved; and the produced (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane has few impurities and high chiral purity, wherein yield can reach 80-90% and HPLC purity is no less than 99%, so product quality is good.

Description

Technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing ivabradine key intermediate (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane. Background technique [0002] Ivabradine and its addition salts with pharmaceutically acceptable acids, especially the preparation method of its hydrochloride salt, are described in European Patent Specification EP0534859, which describes the synthesis method of the compound of formula I: The nitriles are used as raw materials, reduced by borane, and hydrochloric acid is added to obtain the hydrochloride of the amine of formula III, which is then converted into carbamate of formula IV, and then reduced to methylated amine of formula V, and finally with camphor The compound of formula V is resolved by sulfonic acid to produce the compound of formula I. [0003] [0004] The total reaction yield of the above method is extremely low, only 2-3%, and the production co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/347C07C62/34C07B53/00C07B55/00C07B57/00C07C231/02C07C235/40
CPCC07B53/00C07B55/00C07B57/00C07B2200/07C07C51/347C07C231/02C07C2602/06C07C62/34C07C235/40
Inventor 刘雄袁彬黄想亮曹倩姚成志
Owner 安徽美诺华药物化学有限公司
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