Preparation method of mirabegron

An amino, phenylethanol technology, applied in the direction of organic chemistry and other directions, can solve the problems of difficult to realize industrialized production, difficult to obtain starting materials, too long synthesis route, etc., to achieve mild and controllable conditions, broad market prospects and industrial application value , the effect of high reaction yield

Active Publication Date: 2019-04-19
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 produc...

Method used

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  • Preparation method of mirabegron
  • Preparation method of mirabegron
  • Preparation method of mirabegron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] A kind of preparation method of Mirabegron proposed by the present invention comprises the following steps:

[0039] S1, p-nitrophenylacetonitrile is reduced to obtain p-nitrophenylacetaldehyde;

[0040] S2. Condensation and reduction of p-nitrophenylacetaldehyde and (R)-2-amino-1-phenylethanol to obtain (R)-2-((4-nitrophenylethyl)amino)-1-phenyl ethanol;

[0041] S3. Reducing (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol to obtain the intermediate (R)-2-((4-aminophenethyl)amino )-1-phenylethanol;

[0042] S4. Condensing (R)-2-((4-aminophenethyl)amino)-1-phenylethanol with aminothiazoleacetic acid to obtain Mirabegron.

Embodiment 2

[0044] A kind of preparation method of Mirabegron proposed by the present invention comprises the following steps:

[0045] S1, p-nitrophenylacetonitrile is obtained through reduction reaction with diisobutylaluminum hydride as a reducing agent to p-nitrophenylacetaldehyde; wherein, the molar ratio of diisobutylaluminum hydride to p-nitrophenylacetonitrile is 1.1:1 ;

[0046] S2. With diethylamine and 4-N,N-lutidine as catalysts, p-nitrophenylacetaldehyde and (R)-2-amino-1-phenylethanol are condensed and reduced by potassium borohydride, wherein the condensation The reduction temperature is -78°C to obtain (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol;

[0047] S3. Reducing (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol to obtain the intermediate (R)-2-((4-aminophenethyl)amino )-1-phenylethanol; wherein, the reaction system in the reduction reaction is ammonium formate-Pd / C system; the reduction reaction temperature is 10°C, and the reduction reaction time is 8 hours;

...

Embodiment 3

[0050] A kind of preparation method of Mirabegron proposed by the present invention comprises the following steps:

[0051] S1, p-nitrophenylacetonitrile is obtained through reduction reaction with diisobutylaluminum hydride as a reducing agent to p-nitrophenylacetaldehyde; wherein, the molar ratio of diisobutylaluminum hydride to p-nitrophenylacetonitrile is 1.5:1 ;

[0052] S2. Using pyridine as a catalyst, p-nitrophenylacetaldehyde and (R)-2-amino-1-phenylethanol are condensed and reduced by sodium triacetoxy borohydride, wherein the condensation reduction temperature is 50° C. to obtain (R )-2-((4-nitrophenethyl)amino)-1-phenylethanol;

[0053] S3. Reducing (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol to obtain the intermediate (R)-2-((4-aminophenethyl)amino )-1-phenylethanol; wherein, the reaction system in the reduction reaction is ammonium formate-Pd / C system; the reduction reaction temperature is 65°C, and the reduction reaction time is 2 hours;

[0054] S4. Usin...

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Abstract

The invention discloses a preparation method of mirabegron, and the method comprises: S1, carrying out reduction reaction on p-nitrophenylacetonitrile to obtain p-nitrophenylacetaldehyde; S2, carryingout condensation reduction on the p-nitrophenylacetaldehyde and (R) 2-amino-1-phenethyl alcohol to obtain (R) 2-(4-nitrophenethyl) amino)-1-phenyl ethyl alcohol; S3, carrying out reduction on the (R)2-amino-1-phenethyl alcohol to obtain (R) 2-(4-nitrophenethyl) amino)-1-phenyl ethyl alcohol to obtain an intermediate (R) 2-((4-aminophenyl ethyl) amino)-1-phenyl ethyl alcohol; and S4, carrying outcondensation on the (R) 2-((4-aminophenyl ethyl) amino)-1-phenyl ethyl alcohol and aminothiazole acetic acid to obtain the mirabegron. According to the method, the starting raw materials are cheap and easy to obtain, the reaction conditions are controllable, the synthetic route steps are few, the yield is high, the cost is low, and the prepared mirabegron is high in purity.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations, 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 incl...

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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