Concise Synthesis of Key Intermediate of Mirabegron via a Mixed Anhydride Method

Abstract

An efficiently scalable synthesis of key intermediate toward mirabegron has been developed via a mixed anhydride method, employing PivCl instead of EDCI and HOBt. The developed process produced (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (10) in 91.5–92.3% yield and >99.0% HPLC purity under mild conditions. During this process, a side reaction induced by triethylamine hydrochloride was discovered and investigated, which was ultimately avoided by executing the reaction in a biphasic solvent system.

Investigation of Mechanistic Pathway for Trimethyl Borate Mediated Amidation of (R)-Mandelic Acid for the Synthesis of Mirabegron, an Antimuscarinic Agent

“…3 The drug developed by Astellas Pharma was approved by the United States Food and Drug Administrative (US-FDA) in June 2012 and by European Medicines Agency in December 2012. 4 The first generation syntheses, 5 reported two synthetic approaches for 1 (Scheme 1, route a and b) wherein both the approaches follow opening of epoxide ring of the (R)-styrene oxide (8). The first approach (Scheme 1, route a) involves nucleophilic addition of 2 on 8 to obtain nitro amine 5a.…”

“…However, detailed synthetic procedure for the route b is not provided in the report. Both of these approaches have several disadvantages such as extensive use of protecting and de-protecting sequences, expensive (R)-styrene oxide (8) as the starting material, and poor yields for epoxide ring opening reactions.…”

“…Though the second generation synthesis represents an improvement over the first generation, it still has disadvantages, like the use of expensive EDCI in two steps which also poses increased burden of impurities due to side product formation from EDCI and HOBt. Other methods reported for 1 either involve use of expensive (R) -styrene oxide (8) as the starting material resulting in low yields (around 11% to 27%) or involve protection and de -protection steps that make the synthesis lengthy and less economic. 7 Recent reported approach for the synthesis of 4 replaced EDCI and HOBt with pivaloyl chloride (PivCl) for the condensation of amine 2 with acid 3 via mixed anhydride approach in a biphasic medium comprising dichloromethane (DCM) and water in the presence of triethylamine at reflux temperature (Scheme 2).…”

Study on a New Method for Synthesis of Mirabegron

“…Mirabegron, ( 1 , ( R )‐2‐(2‐aminothiazol‐4‐yl)‐4′‐[2‐[(2‐hydroxy‐2‐phenylethyl)amino]ethyl] acetanilide) is a first‐in‐class, potent β 3 ‐adrenergic receptor agonist discovered and developed by Astellas. In June 2012, it was approved by Food and Drug Administration (FDA) as a treatment for overactive bladder with symptoms of urgency, frequency, and leakage in adults . Mirabegron is used as a first‐line treatment drug for its distinctive result, little side effects, and a clear mechanism of action .…”

“…). In method A, compound 4 is prepared from compounds 2 and 3 via dehydration synthesis and then is converted to compound 5 via carbonyl‐extrusion reaction over BF 3 ‐THF and 1,3‐Dimethyl‐2‐imidazolidinone (DMI) . The drawback of this method is that the reagents BF 3 ‐THF and DMI are both environmental hazards and harmful to human health.…”