合成路线1

The reaction of 2,3-dihydrobenzofuran (I) with dichloromethyl methyl ether (II) by means of TiCl4 in dichloromethane gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of NaH in THF to yield the propenoic ester (V). The reduction of (V) with H2 over Pd/C in ethanol affords the saturated propionic ester (VI), which is brominated with Br2 in HOAc providing the 7-bromo derivative (VII). Further bromination of (VII) with Br2 and Fe in HOAc gives the 6,7-dibromo derivative (VIII), which is hydrolyzed with NaOH in THF/water to yield the propionic acid derivative (IX). The reaction of (IX) with hot SOCl2 affords the corresponding acyl chloride (X), which is cyclized by means of AlCl3 in dichloroethane to provide 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The debromination of (XI) by means of H2 over Pd/C in Ac-OH gives 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XII), which is condensed with the phosphorane (XIII) by means of NaH in THF to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV). The selective reduction of the cyano group of (XIV) by means of H2 over Raney cobalt in ethanol/NH3 affords 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XV), which is condensed with propionyl chloride (XVI) by means of TEA in THF to provide the propionamide (XVII). Finally this compound is enantioselectively reduced with H2 over a chiral Ru catalyst (Ru(OAc)2-(S)-BINAP) in methanol to give rise to the target (S)-enantiomer. Alternatively, the reduction of 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV) with H2 over RaNi in ethanol/NH3 gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethylamine (XVIII), which is acylated with propionyl chloride (XVI) and TEA in DMF to yield the racemic propionamide (XIX). Finally this compound is submitted to optical resolution by means of chiral HPLC to afford the target (S)-enantiomer.

合成路线2

The reaction of 2,3-dihydrobenzofuran (I) with DMF (II) and POCl3 gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of t-BuONa in toluene to yield the acrylate (V). The reduction of (V) with H2 over Pd/C in AcOH affords the corresponding propionate (VI), which is brominated with Br2 in AcOH to provide the dibromo derivative (VII). The hydrolysis of the ester group of (VII) in acidic medium gives the expected propionic acid derivative (VIII), which is treated with SOCl2 in dichloromethane to yield the propionyl chloride (IX). The cyclization of (IX) by means of AlCl3 in dichloromethane affords the 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (X), which is submitted to an hydrogenolytic debromination with H2 over Pd/C in methanol to provide the 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The Wittig condensation of (XI) with phosphonate (XII) by means of NaOMe in toluene gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIII), which is reduced with H2 and Raney-Co in toluene/MeOH to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XIV). The asymmetric reduction of (XIV) with H2 and a chiral Ru catalyst in toluene/MeOH affords the 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8(S)-yl)ethylamine (XV), which is finally acylated with propionyl chloride (XVI) and NaOH in aq. THF to provide the target chiral propionamide.

合成路线3