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Preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane

A technology of dimethoxybenzene and methylaminomethyl, applied in the field of pharmaceutical preparation, can solve the problems of difficult industrialization, difficult reaction control, complicated post-processing, etc., and achieves removal of reagents and steps, low production cost, and easy operation. Effect

Inactive Publication Date: 2011-11-23
SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are obvious defects in this method: the relatively toxic ethyl chloroformate reagent is used in the preparation process, and two-step reduction is required. The cyano group reduction is relatively difficult, and it is difficult to react with borane and other toxic, difficult-to-operate reagents. Control and post-processing are complicated, and it is difficult to realize industrialization

Method used

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  • Preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane
  • Preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane
  • Preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane

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Experimental program
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Effect test

Embodiment 1

[0029] Embodiment 1: the synthesis of 4,5-dimethoxy-1-carboxybenzocyclobutane (compound IV)

[0030] 6 grams of 4,5-dimethoxy-1-cyanobenzocyclobutane (compound V) was added to 24 milliliters of potassium hydroxide in ethanol (2 mol / liter), and the temperature was controlled at 10-25 ℃, stirred overnight, added 8 ml of water, and refluxed for 3 hours. After cooling to 0-5°C with an ice-water bath, pour into 200 ml of water. Add 10 ml of concentrated hydrochloric acid, adjust the pH to 4-5, stir for 2 hours, filter, wash the filter residue with 100 ml of toluene, and vacuum-dry at 50°C for 24 hours. 6.0 g of a white solid (Compound IV) was obtained with a yield of 90%.

Embodiment 2

[0032] Add 20 grams of 4,5-dimethoxy-1-carboxybenzocyclobutane and 12 grams of (S)-(-)-α-phenethylamine into 200 ml of ethanol, stir, heat, and reflux for 2 hours , stop stirring, stop heating, cool down to 10-25°C, let stand for 5-10 hours, filter, take the solid, add 150 ml of ethanol, heat, reflux for 0.5 hours, stop stirring, stop heating, cool down to 10-25°C, Stand still for 5-10 hours, filter, adjust the solid to pH = 1.0 with dilute hydrochloric acid, and filter to obtain 8.2 g of white solid (Compound III), yield 41%;

[0033] e.e value: >99%

[0034] MS (ESI): 209 (M+1)

[0035] 1 HNMR (CDCl 3 ): δ 3.38 (2H, m), 3.83 (6H, s), 4.22 (2H, t, J=4Hz), 6.69 (s, 1H), 6.75 (s, 1H).

Embodiment 3

[0037] 20 grams of 4,5-dimethoxy-1-carboxybenzocyclobutane and 30 grams of cinchonidine were added to 300 milliliters of ethanol, stirred, heated, refluxed for 2 hours, stopped stirring, stopped heating, and cooled to 10-25°C, stand still for 5-10 hours, filter, take the solid, add 200 ml of ethanol, heat, reflux for 0.5 hours, stop stirring, stop heating, cool down to 10-25°C, stand still for 5-10 hours, filter, The solid was adjusted to pH = 1.0 with dilute hydrochloric acid, and filtered to obtain 6.7 g of white solid (Compound III), with a yield of 34%;

[0038] e.e value: >95%

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Abstract

The invention provides a preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane (compound I). The preparation method comprises the following steps that (S)-4, 5-dimethoxy benzocyclobutyl-1-carboxylic acid (compound III) is prepared through the split of 4, 5-dimethoxy-1-carboxyl benzocyclobutane (compound IV); then compound III obtained from the previous step undergoes a condensation reaction to form 4, 5-dimethoxy-1-methylaminoformyl benzocyclobutane (compound II); and compound II obtained from the previous step undergoes a reduction reaction to form 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane (compound I). The preparation method has the advantages of less reduction steps, no need of reagents such as ethyl chloroformate and the like, simple and convenient processes, low production cost and great application values.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a preparation method of key intermediate 1-(S)4,5-dimethoxy-1-methylaminomethylbenzocyclobutane in the synthesis of medicine ivabradine. Background technique [0002] Ivabradine (Ivabradine) is a drug developed by Swiss Sewell Company (also known as Servier Company) for the treatment of chronic stable angina pectoris with contraindication or intolerance to β-blockers and normal sinus rhythm . Its chemical name is: (+)-3-[3-[N-[4,5-dimethoxybenzocyclobutanyl-1(S)-methyl]-N-methylamino]propyl ]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzopyrin-2-one hydrochloride. Formula VI is as follows: [0003] [0004] Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated ion channel (I f ) selective blocker, which belongs to HCN (hyperpolarization activated cyclic nucleotidegated) ion channel family. I f Current is a kind of cardiac pacing current, which is mainly involved in the ...

Claims

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Application Information

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IPC IPC(8): C07C217/74C07C213/02
Inventor 黄悦陈春根黄建勋匡泉洪赟飞
Owner SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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