Development of a Ruthenium Catalyzed Asymmetric Hydrogenation for fasiglifam (TAK-875) process: An Approach to the Trace Catalyst Loading

Yamada Masatoshi, Goto Mitsutaka, Konishi Takahiro, Yamashita Masayuki, Kondo Yuichiro, Yamano Mitsuhisa

doi:10.5059/yukigoseikyokaishi.75.432

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fasiglifam（TAK-875）合成中間体の触媒的不斉水素化反応の開発：触媒量の低減への道のり
fasiglifam (TAK-875)ゴウセイチュウカンタイノショクバイテキフセイスイソカハンノウノカイハツ : ショクバイリョウノテイゲンエノミチノリ

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Abstract

<p>A highly effective synthetic method via ruthenium catalyzed asymmetric hydrogenation was developed for (S)-methyl-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate, a key intermediate in the synthesis of the active pharmaceutical ingredient for GPR40/FFAR1 agonist, fasiglifam (TAK-875). In the 1st generation asymmetric hydrogenation, the cost ratio of a chiral amine ((S)-ADPP) to upgrade for enantiomer excess and the chiral ruthenium catalyst was high in overall manufacturing cost of fasiglifam. We tried to change to an inexpensive chiral amine ((R)-PEA) and reduce the chiral ruthenium catalyst amount. It was important to control the dissolved oxygen in solvent and to purify the substrate as a (R)-PEA salt. As a result, we successfully reduced the asymmetric catalyst amount to s/c 20,000 by application of the ruthenium catalyst and the changing substrate form under the tightly controlled conditions (2nd generation asymmetric hydrogenation). Finally, this manufacturing process was successfully performed at commercial scale.</p>

Journal

Journal of Synthetic Organic Chemistry, Japan

Journal of Synthetic Organic Chemistry, Japan 75 (5), 432-440, 2017

The Society of Synthetic Organic Chemistry, Japan

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