Preparation method of Mirabegron

An intermediate, nitrophenethyl technology, applied in the preparation field of mirabegron, can solve problems such as difficulty in realizing industrialized production, difficulty in obtaining starting materials, and excessively long synthetic route, and achieves fewer steps and wider synthetic route. Prospect and industrial application value, good effect of purity

Active Publication Date: 2019-03-12
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] This route is a new route, but it is difficult to realize industrial production because the oxidation of this route uses highly polluting potassium permanganate and the starting materials are not easy to obtain.
[0013] From the above review, it can be known that the synthesis of mirabegron is difficult to realize industrial productio

Method used

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  • Preparation method of Mirabegron
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  • Preparation method of Mirabegron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of S1, intermediate (R)-2-hydroxyl-N-(4-nitrophenethyl)-2-phenylacetamide

[0043] Add 273g (1.64mol, 1.0eq) of p-nitrophenylethylamine, (R)-mandelic acid 250g (1.64mol, 1.0eq) and 1500mL of xylene (mandelic acid V / m is 6), under the protection of nitrogen, the temperature is raised to 140 ° C for reflux, and the reaction is kept for 7 hours. The progress of the reaction is monitored by HPLC. Dissolve methane, wash with 500mL*2 of 5% dilute hydrochloric acid and 500mL*2 of 5% sodium hydroxide respectively, dry the organic phase over anhydrous sodium sulfate, remove dichloromethane under reduced pressure, and obtain the product after drying (R)-2-Hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide is about 429 g, the yield is 87.2%, and the purity is 99.2%.

[0044] Synthesis of S2, intermediate (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol hydrochloride

[0045]Add 400g (1.33mol, 1.0eq) of the intermediate (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide, ...

Embodiment 2

[0051] Synthesis of S1, intermediate (R)-2-hydroxyl-N-(4-nitrophenethyl)-2-phenylacetamide

[0052] Add 273g (1.64mol, 1.0eq) of p-nitrophenylethylamine, (R)-mandelic acid 499g (3.28mol, 2.0eq) and 1750mL of xylene (mandelic acid V / m is 3.5), under the protection of nitrogen, the temperature is raised to 160°C and refluxed, and the reaction is kept for 10 hours. The progress of the reaction is monitored by HPLC. Dissolve methane, wash with 500mL*2 of 5% dilute hydrochloric acid and 500mL*2 of 5% sodium hydroxide respectively, dry the organic phase over anhydrous sodium sulfate, remove dichloromethane under reduced pressure, and obtain the product after drying (R)-2-Hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide is about 450 g, the yield is 91.5%, and the purity is 99.3%.

[0053] Synthesis of S2, intermediate (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol hydrochloride

[0054] Add 400g (1.33mol, 1.0eq) of the intermediate (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetami...

Embodiment 3

[0060] Synthesis of S1, intermediate (R)-2-hydroxyl-N-(4-nitrophenethyl)-2-phenylacetamide

[0061] Add 273g (1.64mol, 1.0eq) of p-nitrophenylethylamine, (R)-mandelic acid 375g (2.46mol, 1.5eq) and 1875mL of dimethylbenzene (mandelic acid V / m is 5), under the protection of nitrogen, the temperature is raised to 150 ° C and refluxed, and the reaction is kept for 9 hours. The progress of the reaction is monitored by HPLC. Dissolve methane, wash with 500mL*2 of 5% dilute hydrochloric acid and 500mL*2 of 5% sodium hydroxide respectively, dry the organic phase over anhydrous sodium sulfate, remove dichloromethane under reduced pressure, and obtain the product after drying (R)-2-Hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide is about 454 g, the yield is 92.3%, and the purity is 99.2%.

[0062] Synthesis of S2, intermediate (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol hydrochloride

[0063] Add 400g (1.33mol, 1.0eq) of the intermediate (R)-2-hydroxy-N-(4-nitrophenethyl)-2-pheny...

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Abstract

The invention discloses a preparation method of Mirabegron and relates to the technical field of medicine preparation. The preparation method includes the steps of subjecting R-mandelic acid and 4-nitrophenylethylamine to amide condensation reaction to obtain an intermediate (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide, reducing amide carbonyl through diisobutyl aluminium hydride to obtainan intermediate (alphaR)-alpha-[[[2-(4-Nitrophenyl)ethyl]amino]methyl]benzenemethanol hydrochloride, reducing nitryl through a ammonium formate-Pd/C reduction system to obtain an intermediate 2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, and finally subjecting the intermediate and (2-aminothiazole-4-yl)acetic acid to condensation reaction to obtain Mirabegron. The Mirabegron prepared by themethod has high purity and high yield; the preparation method needs fewer steps of synthesis route and mild and controllable reaction conditions, is easy and convenient in operation, low in cost andadaptable to industrial production, and has broad prospect and high industrial application value.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of mirabegron. Background technique [0002] Mirabegron was developed by Japan's Astellas Pharmaceutical Company (Astellas), and Yamanouchi Pharmaceutical Co., Ltd. applied for the compound patent of Mirabegron in Japan on October 17, 1997, and protected its preparation method. At present, it has applied for patent protection in many countries and regions such as the United States, Europe, and China. On September 16, 2011, Mirabegron was launched for sale in Japan. In June 2012, it was approved by the US FDA for listing in the United States. As the first orally effective β3 adrenergic receptor agonist drug for the treatment of overactive bladder, the successful marketing of Mirabegron has filled the gap in the treatment of overactive bladder with β adrenergic receptor agonists. [0003] The currently disclosed synthetic routes mainly include the...

Claims

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Application Information

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IPC IPC(8): C07D277/40
CPCC07D277/40
Inventor 黄欢黄庆国李凯施亚琴
Owner ANHUI QINGYUN PHARMA & CHEM
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