Synthesis method of mirabegron

Abstract

The invention provides a synthesis method of mirabegron and belongs to the technical field of medicine synthesis. The synthesis method solves the problems that the synthesis method of the mirabegron is low in product yield and is not suitable for large-scale industrialized production in the prior art. The synthesis method comprises the following steps: 1) amino protection: reacting 2-aminothiazole-5-acetic acid with an amino protective agent to obtain a mirabegron intermediate product A; 2) condensation reaction: performing condensation reaction on the mirabegron intermediate product A and 4-amino phenethyl alcohol to obtain a mirabegron intermediate product B; 3) oxidation reaction: performing oxidation reaction on the mirabegron intermediate product B and an oxidant to obtain a mirabegron intermediate product C; and 4) reductive amination and protecting group removal: reacting the mirabegron intermediate product C with (R)-2-amino-1-phenethyl alcohol and removing the protecting group from the mirabegron intermediate product C to obtain the mirabegron. The synthesis method of the mirabegron is low in cost, high in product yield and suitable for large-scale industrialized production.

Description

technical field [0001] The invention relates to a 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-phe nylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide, the chemical structure 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] or [0009] [0010] However, the...

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Problems solved by technology

[0011] 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

[0012] 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

[0013] 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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