Nippon Roche Research Center

We gratefully acknowledge the contributions to this work of Dr. John F. Blount and Mr. Louis Todaro (X-ray results and ORTEP figures), Dr. Arnold B. Davidson and Mr. Edward Boff results), and Dr. Robert O Brien and Mr. Go binding results), and Drs. David Coffen and Urs Hengartner (process research) all of Hoffmann-La Roche, Nutley. We especially thank Drs. K. Nakamura and I. Kuruma (JH-Ro 22-1319 binding results) of the Nippon Roche Research Center, Kamakura. 

The de novo discovery synthesis of capecitabine (1) was reported by the Nippon Roche Research Center scientists9,19 and was followed up with a preparation invented by a team at the Hoffinann-La Roche laboratories in New Jersey for the conversion to 1 from 5 -DFCR (10).2° In the first route, 5-fluorocytosine (15) was mono-silated using one equivalent of hexamethyldisilazane in toluene at 100 °C followed by stannic chloride-catalyzed glycosidation with known 5-deoxy-l,2,3-tri-0-acetyl-p-D-ribofuranoside (17) in ice-cooled methylene chloride. While this procedure provided the 2, 3 -di-0-acetyl 5-fluorocytidine 18 in 76% yield on a 25-g scale, an alternative method was also devised using in situ-generated trimethylsilyl iodide in acetonitrile at 0°C to provide a 49% yield of 18 on smaller scale. Acylation of the N -amino group of the bis-protected 5 -DFCR derivative was accomplished by the slow addition of two equivalents of -pentyl chloroformate to a solution of 18 in a mixture of pyridine and methylene chloride at -20 °C, followed by a quench with methanol at room temperature to provide the penultimate intermediate 19 on 800-g scale. The yield of intermediate 19 was assumed to be quantitative and was subjected to the final deprotection step, with only a trituration to... 

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See also in sourсe #XX -- [ ]

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