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High-purity key intermediate for preparing formoterol and preparation thereof

A white solid, methoxyphenyl technology, applied in the preparation of organic compounds, chemical instruments and methods, preparation of amino hydroxyl compounds, etc., can solve the problems of isomerism and increased content of optical isomers, and achieve high optical purity , Low consumption cost, simple post-processing effect

Inactive Publication Date: 2014-05-07
BEIJING D VENTUREPHARM TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Our experimental studies have shown that partial isomerization occurs during the preparation of compounds of formula I by ring-opening reactions of epoxides, resulting in an increase in the content of optical isomers by 10-13%

Method used

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  • High-purity key intermediate for preparing formoterol and preparation thereof
  • High-purity key intermediate for preparing formoterol and preparation thereof
  • High-purity key intermediate for preparing formoterol and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 20g (R)-α-(bromomethyl)-4-benzyloxy-3-nitrobenzyl alcohol and 14.6g (R)-4-methoxy-α-methyl-N - (benzyl) phenethylamine, add 200ml of ethanol, and heat to reflux. The reaction was detected by TLC, and the solvent was recovered under reduced pressure after the reaction was completed. The residue was recrystallized with ethanol, filtered with suction, and the filter cake was dried to constant weight to obtain 20.4 g of white solid, namely (R, R)-α-[[[2-(4-methoxyphenyl)-1-methoxyphenyl) phenylethyl](benzyl)amino]methyl]-3-nitro-4-(benzyloxy)-benzyl alcohol, the yield was 68.2%, and the optical purity by HPLC was 97.5%.

Embodiment 2

[0024] Add 20g (R)-α-(bromomethyl)-4-benzyloxy-3-nitrobenzyl alcohol and 14.6g (R)-4-methoxy-α-methyl-N -(Benzyl)phenethylamine, add 200ml of chloroform, and heat to reflux. The reaction was detected by TLC, and the solvent was recovered under reduced pressure after the reaction was completed. The residue was recrystallized with ethanol, filtered with suction, and the filter cake was dried to constant weight to obtain 18.4 g of white solid, namely (R, R)-α-[[[2-(4-methoxyphenyl)-1-methoxyphenyl) Ethyl](benzyl)amino]methyl]-3-nitro-4-(benzyloxy)-benzyl alcohol, the yield was 61.8%, and the optical purity by HPLC was 96.8%.

Embodiment 3

[0026] Add 20g (R)-α-(bromomethyl)-4-benzyloxy-3-nitrobenzyl alcohol and 14.6g (R)-4-methoxy-α-methyl-N -(Benzyl)phenethylamine, add 200ml N,N-dimethylformamide, and control the reaction temperature at 90-100°C. The reaction was detected by TLC, and the solvent was recovered under reduced pressure after the reaction was completed. The residue was recrystallized with ethanol, filtered with suction, and the filter cake was dried to constant weight to obtain 17.7 g of white solid, namely (R, R)-α-[[[2-(4-methoxyphenyl)-1-methoxyphenyl) Ethyl](benzyl)amino]methyl]-3-nitro-4-(benzyloxy)-benzyl alcohol, the yield was 59.2%, and the optical purity by HPLC was 95.9%.

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Abstract

The invention discloses a high optical purity compound (R, R)-alpha-(((2-(4-methoxy phenyl)-1-methyl ethyl)(benzyl)amino)methyl)-3-nitryl-4-(benzyloxy)-benzyl alcohol (compound shown in formula I) and a preparation method thereof; wherein the compound is a key intermediate for preparing (R, R)-Formoterol. The formula I is shown in the description.

Description

technical field [0001] The present invention relates to a high optical purity compound (R, R)-α-[[[2-(4-methoxyphenyl)-1-methylethyl](phenylmethyl)amino]methyl]- 3-Nitro-4-(benzyloxy)-benzyl alcohol and a process for its preparation. Background technique [0002] Formoterol is a novel beta 2 - Adrenergic receptor agonists for the treatment of chronic bronchial asthma, nocturnal asthma, exercise-induced asthma, chronic obstructive pulmonary disease and non-asthmatic airway diseases in children. There are two chiral centers in the formoterol molecule, and each chiral center may have two configurations. Therefore, the formoterol molecule can have four configurations, namely (R, R), (S, S) , (R, S) and (S, R), and the (R, R) configuration has the best biological activity. Formoterol is mainly used clinically as a pair of racemates with (R, R) and (S, S) configurations of fumarate hydrate. The compound provided by the present invention is an important intermediate for the pre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/70C07C213/04
Inventor 李雪梅
Owner BEIJING D VENTUREPHARM TECH DEV