Synthetic method of mirabegron

Abstract

The invention discloses a synthetic method of mirabegron, which comprises the following steps: 1)amine-ester exchange reaction: taking (R)-mandelic ester and 4-nitrophenethylamine as raw materials for an ester interchange reaction to obtain a mirabegron intermediate A; 2)amide reduction: reducing amide of the mirabegron intermediate A to obtain a mirabegron intermediate B; C)nitro reduction: performing a reduction reaction of the mirabegron intermediate B and a reducing agent stannous chloride to obtain a mirabegron intermediate C; and D)condensation reaction: performing a condensation reaction of the mirabegron intermediate C and 2-aminothiazole-4-acetate under the effect of a condensing agent to obtain mirabegron. The synthetic method has the advantages of low cost of raw material and high yield of product, and is suitable for large scale industrial production.

Description

technical field [0001] The present invention relates to a kind of synthetic method of chemical medicine, especially a kind of synthetic method of mirabegron. Background technique [0002] Mirabegron (Myrbetriq, Mirabegron) is a drug approved by the US Food and Drug Administration (FDA) on June 28, 2012 for the treatment of overactive bladder (OAB). Overactive bladder is a disease characterized by urgency, frequency, and urge incontinence. According to the US FDA statistics, about 33 million people suffer from this disease. [0003] English name of Mirabegron: [0004] 2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino] ethyl]phenyl] -4-thiazoleacetamide, the chemical structural formula is: [0005] [0006] In the prior art, the synthesis of mirabegron uses expensive borane-tetrahydrofuran solution, 1,3-dimethyl-2-imidazolidinone, palladium carbon, the production cost is high, the raw materials are not easy to obtain, and 1,3-Dimethyl-2-imidazolidinone and borane-tet...

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Problems solved by technology

[0006] In the prior art, the synthesis of mirabegron uses expensive borane-tetrahydrofuran solution, 1,3-dimethyl-2-imidazolidinone, palladium carbon, the production cost is high, the raw materials are not easy to obtain, and 1,3-Dimethyl-2-imidazolidinone and borane-tetrahydrofuran solution are not easy to recycle and apply mechanically, resulting in increased cost of raw materials and post-processing, which is not conducive to large-scale industrial production; and toxic toluene needs to be used in the synthesis process It is a solvent for recrystallization, and the borane-tetrahydrofuran solution used has a foul smell at room temperature, is sensitive to moisture, reacts violently with water, and will release flammable gases to form explosive peroxides, and this gas is harmful to the eyes, respiratory system and The skin is irritating, which is very unfavorable to operators and the ecological environment; and the post-reaction treatment steps in the existing synthetic methods are cumbersome, and it is easy to produce a large amount of three wastes, and due to the expensive 1,3-dimethyl-2-imidazoline The ketone reagent has a high boiling point (224-226°C) and is difficult to remove, so the yield of this synthesis method is low

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