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

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 aldehyd...

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Bibliographic Details
Published inOrganic process research & development Vol. 15; no. 5; pp. 1163 - 1171
Main Authors Fox, Martin E, Jackson, Mark, Meek, Graham, Willets, Matthew
Format Journal Article
LanguageEnglish
Published American Chemical Society 16.09.2011
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/op200129m