Discovery research devising syntheses

The chemists responsible for providing these 12 kilos consider using the unoptimized synthesis devised by discovery researchers. If the process chemists do operate it, they do so because time constraints prevent them from improving or circumventing it. It entails six chemical steps, we again suppose, each one proceeding in an average yield of 50%. 

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... 

It was quite clear that the scale of production in the William Dunn School could barely provide enough material for further clinical trials hence, Florey tried to elicit the help of drug companies. ICI, Burroughs Wellcome, Boots and a small London company, Kemball-Bishop, all showed interest but due to the exigencies of war-tom Britain, none had sufficient funds for speculative research. They were probably also worried that a chemical synthesis of penicillin would be devised once its structure had been elucidated thus, money spent on culture technology would be wasted. They were also probably worried about the patent situation. Florey had mentioned this issue to the Medical Research Council, which had provided a modest amount of research money. Apparently, the senior MRC officials were vehemently opposed to patenting on the grounds that it was unethical for medical researchers to benefit from their discoveries. The American pharmaceutical companies suffered no such qualms of conscience, and in due course the British companies had to pay royalties to their US counterparts before they could produce penicillins. 

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