Large-Scale Synthesis of a Substituted d-Phenylalanine Using Asymmetric Hydrogenation

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• 作者：Martin E. Fox ; Mark Jackson ; Graham Meek ; Matthew Willets
• 刊名：Organic Process Research & Development
• 出版年：2011
• 出版时间：September 16, 2011
• 年：2011
• 卷：15
• 期：5
• 页码：1163-1171
• 全文大小：892K
• 年卷期：v.15,no.5(September 16, 2011)
• ISSN：1520-586X

文摘

A synthetic route to an N-BOC d-phenylalanine pharmaceutical intermediate suitable for rapid scale-up to 150-kg scale was required. A seven-step route based on asymmetric hydrogenation of an N-acetyl dehydroamino-acid was developed. Starting with terephthalic dialdehyde, monoreduction of one aldehyde group, Erlenmeyer condensation, and ring-opening/O-deacetylation with methanol provided the 4-(hydroxymethyl)-substituted dehydrophenylalanine hydrogenation substrate. Asymmetric hydrogenation of this enamide using [((R,R)-Ethyl-DuPhos)Rh(COD)]BF₄ proceeded in high enantiomeric excess. Subsequently, the cis-2,6-piperidyl group was introduced by mesylation/displacement, the BOC group was introduced, and acetyl and methyl ester groups were removed by basic hydrolysis. This route was used to manufacture 150 kg of the BOC amino acid 1.