Abstract
The present work describes investigation of mechanistic pathway for trimethyl borate mediated amidation of (R)-mandelic acid (3) with 4-nitophenylethylamine (2) to provide (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (4) during mirabegron synthesis. Plausible reaction mechanism is proposed by isolating and elucidating the active α-hydroxy ester intermediate 16 from the reaction mass. Trimethyl borate mediated approach proved to be selective in providing 4 without disturbing α-hydroxyl group and stereochemistry of the chiral center, and is also a greener, more economic and production friendly over the reported methods. The developed approach is rapid and efficient for the preparation of 4 with an overall yield of 85-87% and around 99.0% purity by HPLC at scale.
Highlights
Mirabegron (1), chemically known as 2-(2-amino -1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2phenylethyl]amino}ethyl)phenyl]acetamide, is a selective agonist for the human beta 3-adrenoceptor,[1] approved for the treatment of overactive bladder (OAB) syndrome.[2]
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
In continuation of our research on mirabegron (1), we report an easy, straightforward, industrially scalable, selective and economic synthesis of the key intermediate (R)-2-hydroxy-N[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (4) using trimethylborate as the coupling agent
Summary
Mirabegron (1), chemically known as 2-(2-amino -1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2phenylethyl]amino}ethyl)phenyl]acetamide, is a selective agonist for the human beta 3-adrenoceptor,[1] approved for the treatment of overactive bladder (OAB) syndrome.[2]. 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). Aniline 6a is further condensed with thiazole acid 7 to obtain amide intermediate 1a. In the second approach (Scheme 1, route b), condensation of (4-aminophenyl)acetonitrile (9) and thiazole acid 7 is carried out in the first step, whereas advanced intermediate 11a is reacted with epoxide 8 in penultimate step to provide 1. 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
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