Merariveron preparation method

Abstract

The invention discloses a merariveron preparation method which includes the following steps that a, amino protection is carried out, aminobenzyl cyanide and di-tert-butyl dicarbonate react and protect para-position amine to obtain Boc aminobenzyl cyanide; b, nitrile reduction is carried out, hydrogen reduction nitrile is added to the Boc aminobenzyl cyanide under the action of a reduction catalyst of raney nickel or palladium on carbon, and Boc 2-(4-aminophenyl)ethylamine is obtained; c, condensation reaction is carried out, (R)-styrene oxide and the Boc 2-(4-aminophenyl)ethylamine react to obtain (R)-2-((4-Boc amine phenethyl) amine)-1-phenylethanol; d, deprotection is conducted, Boc groups are removed from the (R)-2-((4-Boc amine phenethyl) amine)-1-phenylethanol under the action of trifluoroacetic acid, and (R)-2-((4-amine phenethyl) amine)-1-phenylethanol is obtained; e, ester-amide condensation is carried out, the (R)-2-((4-amine phenethyl) amine)-1-phenylethanol and 2-aminothiazole-4-acetic acid are condensed under the action of a coupling reagent to obtain a target product of merariveron. The method is easy to operate and implement, raw materials are cheap and easy to obtain, reaction efficiency is high, byproducts are few, and repeatability is good.

Description

Technical field [0001] The invention belongs to the technical field of chemical medicine synthesis, and specifically relates to a preparation method of Mirabegron. Background technique [0002] Mirabegron 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 incontinence, urgency, and frequent urination. The English name of Mirabegron is: 2-Amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethy]amino]ethyl]pheny]-4-thiazoleacetamide, and its chemical structure is: [0003] [0004] In the prior art, there are mainly the following methods for the synthesis of Mirabegron: [0005] For example, the European invention patent (EP1440969) relates to the synthesis method of Mirabegron, and its synthesis route is: [0006] [0007] However, the above synthesis method requires the use of expensive borane-tetrahydrofuran solution and 1,3-dimethyl-2-imidazolidinone. Borane-tetrahydrofuran solution has a foul sme...

AI Technical Summary

Problems solved by technology

[0010] Chinese patent (CN103896872A) uses p-nitrophenylethylamine and (R)-styrene oxide as starting materials for ring-opening reaction, and then undergoes reduction and condensation to obtain Mirabegron. Only three steps of reaction are required, and the yield is high , but reduction of (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol (compound a) affords (R)-2-((4-aminophenethyl)amino)-1 - During the process of phenylethyl alcohol (compound b), it is easy to remove the chiral hydroxyl group to obtain a by-product (compound d)

Images