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

山田 雅俊, 後藤 充孝, 小西 隆博, 山下 真之, 近藤 裕一郎, 山野 光久

doi:10.5059/yukigoseikyokaishi.75.432

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タイトル別名

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

収録刊行物

有機合成化学協会誌

有機合成化学協会誌 75 (5), 432-440, 2017

公益社団法人有機合成化学協会

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