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A preparation method of optically pure (+)-ambisentan and optically pure (+)-dalusentan

A compound, the technology of diphenyl acrylate, is applied in the field of preparation of ambesentan and darusentan, which can solve the problems of increased cost, low utilization rate of raw materials, and restrictions on the application of industrial scale of products, so as to increase the income rate, the effect of reducing content

Active Publication Date: 2011-12-14
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As we all know, the resolution of chiral drugs does not have a high utilization rate of raw materials, resulting in an increase in cost and limiting the application of products on an industrial scale

Method used

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  • A preparation method of optically pure (+)-ambisentan and optically pure (+)-dalusentan
  • A preparation method of optically pure (+)-ambisentan and optically pure (+)-dalusentan
  • A preparation method of optically pure (+)-ambisentan and optically pure (+)-dalusentan

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Experimental program
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Effect test

Embodiment 1

[0034] Example 1, (+)-Ambsentan ((2S)-2-[(4,6-dimethylpyrimidin-2-yl)-oxygen]-3-methoxy-3,3-diphenyl propionic acid) preparation

[0035] (1) Preparation of (2S)-3,3-diphenyl-2,3-epoxypropionic acid ethyl ester

[0036]

[0037] The reaction equation is shown in the above formula, wherein, Ph is phenyl; Ac is acetyl;

[0038] Add 3,3-ethyl diphenylacrylate (0.536mol, 135.0g) dissolved in 3.0L acetonitrile to a 50L reaction kettle with a mechanical stirrer, and dissolve in 1.5L acetonitrile to obtain a concentration of 0.12M Fructose-derived chiral ketone shown in formula (IV), and adding tetra-n-butyl ammonium bisulfate (36mmol, 12.2g), then adding 3.0L 1×10 -4 M's disodium ethylenediaminetetraacetic acid aqueous solution; put cooling liquid in the interlayer of the reaction kettle, adjust the temperature in the reaction kettle to -5°C-+5°C; 1.85kg of potassium monopersulfate compound salt and 0.78kg NaHCO 3 (9.29mol) of the mixture, it takes about 4.5 hours to add th...

Embodiment 2

[0052] Example 2, (+)-dalusentan ((2S)-2-[(4,6-dimethoxypyrimidin-2-yl)-oxygen]-3-methoxy-3,3-diphenyl Propionic acid) preparation

[0053] (1) Preparation of (2S)-3,3-diphenyl-2,3-epoxypropionic acid ethyl ester

[0054]

[0055] The reaction equation is shown in the above formula, wherein, Ph is phenyl; Ac is acetyl;

[0056] Add 3,3-diphenyl acrylate ethyl ester (0.267mol, 67.3g) dissolved in 1.5L acetonitrile in the 50L reaction kettle with mechanical stirrer, the concentration obtained in 0.75L acetonitrile is 0.12M Fructose-derived chiral ketone shown in formula (IV), and adding tetra-n-butyl ammonium bisulfate (18mmol, 6.1g), then adding 1.5L 1×10 -4 M's disodium ethylenediaminetetraacetic acid aqueous solution; put cooling liquid in the interlayer of the reaction kettle, adjust the temperature in the reaction kettle to -5°C-+5°C; 0.923kg (1.5mol) potassium hydrogen persulfate compound salt and 0.391 kg NaHCO 3 (4.65mol) of the mixture, it takes about 4.5 hours...

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Abstract

Disclosed is a method for preparing optically pure (+)-ambrisentan and (+)-darusentan, comprising: firstly catalyzing the asymmetric epoxidation of a β-unsaturated alkene using a chiral ketone derived from fructose or a hydrate thereof as a catalyst, and then subjecting the product to an epoxy compound ring-opening reaction and substitution reaction successively to obtain optically pure (+)-ambrisentan and (+)-darusentan.

Description

technical field [0001] The invention relates to a preparation method of optically pure (+)-ambisentan and (+)-dalusentan. Background technique [0002] Ambrisentan and darusentan were first reported (J.Med.Chem.1996, 39, 2123-2128) as a selective endothelin receptor A antagonist, and their pharmacological properties were subsequently further studied , published in (J.Med.Chem.1996, 39, 2123-2128), US Patent US 5932730, WO 2009 / 017777A2. As shown in formula (I), when R is methyl, the Chinese name is (+)-ambisentan, and the Chinese chemical name is (+)-(2S)-2-[(4,6-dimethylpyrimidine -2-yl)-oxy]-3-methoxy-3,3-diphenylpropionic acid; English name (+)-ambrisentan, English name: (S)-2-(4,6-dimethylpyrimidin -2-yloxy)-3-methoxy-3, 3-diphenylpropanoic acid; when R is methoxy, the Chinese name is (+)-dalusentan, and the Chinese chemical name is (+)-(2S)-2-[ (4,6-dimethoxypyrimidin-2-yl)-oxygen]-3-methoxy-3,3-diphenylpropionic acid; the English name is (+)-darusentan, and the Engl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/32C07D239/60
CPCC07D239/32C07D239/34C07D239/60
Inventor 史一安彭先友李培军
Owner INST OF CHEM CHINESE ACAD OF SCI
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