Tetrahydrofuran → Tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate

Beteiligte Stoffe

Reaktionsschritte

Scheme 4 and 5 show routes for preparation of compound of formula 2b. The protected amino acid is either commercially available material or prepared as described in known literature. For example, the CBZ protected (2S,3S)-hydroxyleucine (CBZ: benzyloxycarbonyl) is prepared according to the analogous procedure to that described in the literature (Panek, J., J. Org. Chem., 1998, 63, 2382). As shown in scheme 4, phenylglycinol is alkylated with tert-butyl bromoacetate in the presence of base such as triethylamine in a solvent such as anhydrous tetrahydrofuran, to provide tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate. Reaction of tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate and diphenylacetaldehyde in the presence of a drying agent such as magnesium sulfate in a solvent such as anhydrous methylene chloride provides tert-butyl (2-benzhydryl-4-phenyl-oxazolidin-3-yl)-acetate. The oxazolidine is treated with a nucleophile such as lithium diisopropylamide in an anhydrous solvent such as anhydrous tetrahydrofuran at low temperature such as −78° C., followed by addition of an electrophile such as isopropylaldehyde, to provide tert-butyl 2-(2-benzhydryl-4-phenyl-oxazolidin-3-yl)-3-hydroxy-4-methyl-pentanoate. The oxazolidine ring is cleaved by treatment with acid such as formic acid in a solvent such as a mixture of water and tetrahydrofuran to provide tert-butyl 3-hydroxy-2-(-2-hydroxy-1-phenyl-ethylamino)-4-methyl-pentanoate. The amine is freed by hydrogenolysis using catalyst such as 5-10% palladium on carbon in a solvent such as methanol or ethanol, to provide tert-butyl 2-amino-3-hydroxy-4-methyl-pentanoate. The resulting free amine is protected by treatment with an agent such as (benzyloxycarbonyloxy)succinimide or benzyloxycarbonyl chloride in a solvent such as anhydrous methylene chloride, then the ester is cleaved by treatment with an acid such as trifluoroacetic acid to provide 2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid. Optically pure compound can be prepared by using an optically pure starting material. For example, optically pure (S)-phenylglycinol provides (2S,3S)-2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid.

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