S-9490 is synthesized by coupling (2S,3aS,7aS)-2-tert-butoxycarbonylperhydroindole (II) with N-[(S)-1-carbethoxybutyl-(S)-alanine (I).
An asymmetric synthesis of pregabalin has been reported: Condensation of isobutyraldehyde (I) with acrylonitrile (II) by means of DBU and 2,6-di-tert-butyl-4- methylphenol (DBP) gives 3-hydroxy-4-methyl-2-methylenepentanenitrile (III), which is acylated with AcCl or Ac2O and pyridine to yield the acetate (IV). The carboxylation of (IV) by means of Pd(OAc)2, PPh3, CO and EtOH affords 3-cyano-4-methyl-3-hexenoic acid ethyl ester (Va-b), which is hydrolyzed with KOH in THF/water to provide the corresponding carboxylic acid potassium salt (VIa-b). Acidification of (VIa-b) with HCl, followed by reaction with tert-butylamine gives the corresponding salt (VIIa-b), which is reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)-Rh] in THF/water to yield (S)-3-cyano-5-methylhexanoic acid butylammonium salt (VIII). Finally, the CN group of (VIII) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol. Alternatively, intermediate (VIa-b) can be reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)-Rh] in THF/water to yield (S)-3-cyano-5-methylhexanoic acid potassium salt (IX). Finally, the CN group of (IX) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol.
[U-14C]-Aniline (I) is converted to [U-14C]phenyldiazonium chloride (II), which is condensed in situ with ethyl 2-(ethoxyalyl)propionate (III) to give [U-14C]phenylhydrazone of ethyl pyruvate (IV). Cyclization of (IV) by polyphosphoric acid in xylene affords ethyl [U-14C-phenyl]indole-2-carboxylic acid (V). Catalytic hydrogenation of compound (V) in the presence of platinum gives ethyl [U-14C-cyclohexyl]-(RS)-perhydroindole-2-carboxylic acid (VI), which is saponified to the corresponding acid (VIII). Compound (VI) can also be prepared by reduction of compound (V) with tin and hydrochloric acid to give compound (VII), and hydrogenation of the latter in the presence of palladium. Compound (VIII) is reesterified to the benzyl ester (IX), which is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine (X) in the presence of DCC and 1-hydroxy-1-benzotriazole. The resulting compound (X) is separated fom the mixture of isomers by silica gel column chromatography. Hydrogenolysis of the latter compound gives [U-14C-cyclohexyl]perindopril, which is isolated as the tert-bytylamine salt.