Large-scale synthesis of 1,1,3,3,6-pentamethyl-1,3-disilaindan-5-ol via a CoBr2/Zn-catalyzed [2+2+2] cycloaddition reaction |
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Authors: | Ryo Mizojiri Richard Conroy Etsuo Kotani David Miller Tetsuji Kawamoto |
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Institution: | a Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 2-17-85 Jusohonmach, Yodogawa-ku, Osaka 532-8686, Japan b Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, D-97074 Würzburg, Germany c Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge CB4 0PA, UK |
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Abstract: | 1,1,3,3,6-Pentamethyl-1,3-disilaindan-5-ol (2) is a key intermediate in the synthesis of new sila-substituted gonadotropin releasing hormone receptor antagonists, such as 1. In order to produce sufficient quantities of 1 for pharmacological and toxicological evaluation, an efficient synthesis of 2 has been developed. (1,1,3,3,6-Pentamethyl-1,3-disilaindan-5-yl)methanal (11) was synthesized in a one-pot procedure. CoBr2/Zn-catalyzed 2+2+2] cycloaddition of diyne 3 with the commercially available monoalkyne 15 was achieved through a slow addition of 3 and CoBr2 to a mixture of 15 and zinc powder in refluxing acetonitrile, giving rise to 5-(diethoxymethyl)-1,1,3,3,6-pentamethyl-1,3-disilaindane (14). In-situ aqueous acidification yielded 11. Conversion to 2 was then achieved via a Baeyer-Villiger oxidation followed by hydrolysis under basic condition. This novel methodology is useful, not only for the rapid, large-scale synthesis of 2, but also for the synthesis and development of new sila-substituted drugs derived from 11. |
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Keywords: | Sila-substituted drug Gonadotropin releasing hormone receptor antagonist 1 1 3 3 6-Pentamethyl-1 3-disilaindan-5-ol Cobalt-catalyzed [2+2+2] cycloaddition reaction Cobalt(II) bromide |
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