Mirabegron preparation method

Abstract

The invention discloses a mirabegron preparation method. The mirabegron preparation method comprises the following steps of a, hydroxy protection: obtaining an (R)-1-phenyl-1,2-hydroxyl-sulfonate compound through an (R)-1-phenyl-1,2-glycol and sulfonyl chloride compound, namely methylsulfonyl chloride or paratoluensulfonyl chloride, under a catalytic action of a basic catalyst-piperidine or triethylamine; b, condensation reaction: obtaining (R)-2-((4-nitrobenzene ethyl) amino)-1-phenethyl alcohol through the (R)-1-phenyl-1,2-hydroxyl-sulfonate compound and p-nitrophenyl ethylamine under a catalytic action of a basic catalyst-potassium carbonate or triethylamine; c, nitro reduction: obtaining a compound, namely (R)-2-((4-aminobenzene ethyl) amino)-1-phenethyl alcohol by carrying out nitro catalyzing and amino reducing on the (R)-2-((4-nitrobenzene ethyl) amino)-1-phenethyl alcohol through reduced iron powder; d, condensation reaction: obtaining a target product-mirabegron through the (R)-2-((4-aminobenzene ethyl) amino)-1-phenethyl alcohol and 2-aminothiazole-4-acetic acid under the action of a coupling agent. The mirabegron preparation method disclosed by the invention has the advantages that the operation is simple and easy, raw materials are low in cost and easily obtained, the reaction efficiency is high, and the repeatability is good.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chemical drugs, and in particular relates to a preparation method of miregluron. Background technique [0002] Milagron is a drug approved by the US Food and Drug Administration (FDA) on June 28, 2012 for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency. [0003] The chemical structural formula of Miregron is: [0004] [0005] In the prior art, the synthetic methods of miregluron mainly contain the following: [0006] For example, the European invention patent (EP1559427) involves the synthesis method of Miregalon, and its synthesis route is: [0007] [0008] However, the above synthesis method requires the use of expensive borane-tetrahydrofuran solution and 1,3-dimethyl-2-imidazolidinone. The borane-tetrahydrofuran solution has a foul smell and reacts violently with water and emits flammable gases. It can form explosive ...

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Problems solved by technology

[0011] Chinese patent (CN103896872A) uses p-nitrophenylethylamine and (R)-styrene oxide as the starting materials for ring-opening reaction, and then undergoes reduction and condensation to obtain miregron. Only three steps of reaction are required, and the yield is high , but the raw material (R)-styrene oxide is very expensive, and the reduction of (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol (compound 1) gives (R)-2- In the process of ((4-aminophenethyl)amino)-1-phenylethanol (compound 2), it is easy to remove the chiral hydroxyl group to obtain a by-product (compound 4). This route is not suitable for industrial production

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