合成路线1

Scheme shows the synthesis of Galardin(TM) from the two starting materials, 4-methyl-2-oxopentanoic acid sodium salt (I) and tert-butyloxycarbonyl-L-tryptophan (V). The pentanoic acid is protected as a benzyl ester and then condensed with the ylide methyl (triphenylphosphoranylidene)acetate to give methyl 3-benzyloxycarbonyl-5-methyl-2-hexenoate (III). Deprotection and reduction of (III) gives the key intermediate 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoic acid (IV) in high overall yield. The protected L-tryptophan starting material (V) is coupled with methylamine to give (VI), which is deprotected to give the second key intermediate, L-tryptophan methylamide hydrochloride (VII). Coupling of (IV) and (VII) gives the mixture of diastereomers 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide. Low-pressure column chromatography on silica gel gives 2(R)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide (VIII) in high yield. Direct hydroxaminolysis of the methyl ester (VIII) in methanol in the presence of potassium hydroxide gives crude Galardin(TM). Recrystallization gives the drug substance.