Significant rate enhancement via potassium pivalate in a Miyaura borylation approach to verinurad
| Autor: | Lyn Powell, Barry R. Hayter, Oliver T. Ring, Andrew D. Campbell |
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| Rok vydání: | 2020 |
| Předmět: |
inorganic chemicals
chemistry.chemical_classification Diethanolamine 010405 organic chemistry Chemistry Potassium Organic Chemistry chemistry.chemical_element Transesterification 010402 general chemistry 01 natural sciences Biochemistry Borylation Combinatorial chemistry 0104 chemical sciences chemistry.chemical_compound Drug Discovery Reactivity (chemistry) Carboxylate Counterion Boronic acid |
| Zdroj: | Tetrahedron Letters. 61:151589 |
| ISSN: | 0040-4039 |
| Popis: | We describe herein the significant rate-enhancing effect of employing potassium pivalate as a base in a Miyaura borylation. The manufacturing route to verinurad currently employs a Suzuki-Miyaura cross-coupling, requiring cryogenic conditions to generate the boronic acid coupling partner. This process has manufacturability challenges including those associated with low temperature operations and thus an alternative Miyaura borylation approach is described. High throughput screening was employed to investigate the effects of various carboxylate bases and their corresponding counterions on reactivity. Our results highlight potassium pivalate as producing exceptional rate acceleration. To the best of our knowledge this base has not previously been reported for use in Miyaura borylations. Diethanolamine transesterification is also reported as a facile and robust boronate isolation protocol. Successful application of this diethanolamine boronate ester in downstream cross-coupling chemistry has demonstrated the potential for this new route in commercial manufacture of verinurad. |
| Databáze: | OpenAIRE |
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