- Synthesis of BACE1 Inhibitors E2609 / E2071 via Oxime-Olefin Cycloaddition following a Process Risk Mitigation Strategy
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Process development of E2609 from the preclinical stage to the clinical stage following a process risk mitigation strategy is described here. Key features include a turbo Grignard reaction monitored by in-situ IR, [3 + 2] cycloaddition in water, chemoselective amide coupling via in-situ protection, and a Reformatsky/decarboxylation approach to install a difluoromethyl group. Toward safe and scalable manufacture of E2071, an analog of E2609, a flow-reaction process for trifluoromethylation of aldehydes is presented here.
- Benayoud, Farid,Bracke, Markus,Chanda, Arani,Dimopoulos, Paschalis,Fang, Francis G.,Farthing, Christopher N.,Hall, Adrian,Ishida, Tasuku,Kaneko, Toshihiko,Kayano, Akio,Khan, Afzal,Kim, Dae-Shik,Kita, Yoichi,Lu, Lily,Mitasev, Branko,Motoki, Takafumi,Nagai, Mitsuo,Omori, Masayuki,Schnaderbeck, Matthew,Suzuki, Yuichi,Takaishi, Mamoru,Takeda, Kunitoshi,Wakasugi, Kazunori,Watanabe, Yuzo,Yamamoto, Noboru,Yoshizawa, Kazuhiro,Zhang, Huiming
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- METHOD FOR PRODUCING 5-(DIFLUOROMETHYL)PYRAZINE-2-CARBOXILIC ACID AND PRODUCTION INTERMEDIATE THEREOF
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5-(Difluoromethyl)pyrazine-2-carboxilic acid, which is a raw material for the construction of 5-(difluoromethyl)pyrazine-2-carboxamide, which is a common partial structural motif of the compound having an A production inhibitory action or a BACE1 inhibitory action, can be industrially advantageously produced by decarboxylating 5-[carboxy(difluoro)methyl]pyrazine-2-carboxylic acid, which is obtainable from 5-chloropyrazine-2-carboxylate.
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Paragraph 0036
(2013/11/18)
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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