Novel synthesis method of mirabegron

Abstract

The invention provides a novel synthesis method of mirabegron, and belongs to the technical field of drug synthesis. The problems that the yield of synthesized mirabegron is low in the prior art, and the method is unsuitable for large-scale industrial production are solved. The synthesis steps are as follows: 1) performing amino protection, namely reacting 2-aminothiazole-4-acetic acid with an amino protective agent to obtain a mirabegron intermediate product A; 2) performing condensation reaction, namely performing the condensation reaction on the mirabegron intermediate product A and the 4-aminophenethanol to obtain the mirabegron intermediate product B; 3) performing oxidizing reaction, namely performing the oxidizing reaction on the mirabegron intermediate product B and an oxidizing agent to obtain the mirabegron intermediate product C; 4) removing protective agent while performing reductive amination, namely reacting the mirabegron intermediate product C with (R)-2-amino-1-phenethanol under the effect of a reducing agent, and meanwhile removing the protective group on the mirabegron intermediate product C to obtain the mirabegron. The novel synthesis method of mirabegron provided by the invention is low in cost, high in product yield and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a new synthesis method of mirabegron, which belongs to the technical field of chemical drug synthesis. Background technique [0002] Mirabegron (Myrbetriq, Mirabegron) was approved by the U.S. Food and Drug Administration (FDA) on June 28, 2012 and is used to treat overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequent urination. drug. [0003] The English name of Mirabegron: 2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide, the chemical structural formula is: [0004] [0005] In the prior art, the synthetic methods for Mirabegron mainly contain the following: [0006] For example, the European Invention Patent (publication number: EP1440969) and the European Invention Patent (publication number: EP1559427) involve the synthesis method of mirabegron, and the synthetic route of the method is as follows: [0007] [0008] However, the above synthe...

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Problems solved by technology

[0009] 1. The two synthetic methods simultaneously use expensive borane-tetrahydrofuran solution, 1,3-dimethyl-2-imidazolinone, palladium carbon, and 1,3-dimethyl-2-imidazoline Ketone and borane-tetrahydrofuran solutions are not easy to recycle and apply mechanically, resulting in increased raw material and post-processing costs, which is not conducive to large-scale industrial production

[0010] 2. The first step of these two synthetic methods needs to use toxic toluene as a solvent for recrystallization; the borane-tetrahydrofuran solution used in the second step is a liquid at normal temperature, has a foul smell, is sensitive to moisture, and reacts violently with water And release flammable gas, which can form explosive peroxides, and is irritating to eyes, respiratory system and skin, which is not good for operators and ecological environment

[0011] 3. After the first step of the two synthetic methods is completed, the reaction solution needs to be washed with water, pickled, alkali washed, washed with brine, and recrystallized to obtain the pure product. 1,3-dimethyl-2-imidazolidinone reagent with high boiling point (224-226°C) that is difficult to remove, so the yield of this synthesis method is low

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