Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant
| Autor: | Justin Belardi, Lushi Tan, Bangping Xiang, Nobuyoshi Yasuda, Ed Cleator, John S Edwards, Chen Frank, Lisa DiMichele, Kevin M. Belyk, Fabien L. Cabirol, Scott S. Ceglia, Jianguo Yin, Shen-Chun Kuo, Peter R Mullens, Weng Lin Tang, Adrian Goodyear, Guiquan Liu, Zhiguo Jake Song, Robert A. Reamer, Birgit Kosjek, Brian Bishop |
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| Rok vydání: | 2017 |
| Předmět: |
chemistry.chemical_classification
010405 organic chemistry Transamination Stereochemistry Organic Chemistry Enantioselective synthesis Diastereomer Calcitonin gene-related peptide 010402 general chemistry 01 natural sciences 0104 chemical sciences Stereocenter chemistry.chemical_compound chemistry Lactam Peptide bond Physical and Theoretical Chemistry Phase-transfer catalyst |
| Zdroj: | Organic Process Research & Development. 21:1851-1858 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.7b00293 |
| Popis: | The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant. |
| Databáze: | OpenAIRE |
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