合成路线1

Reaction of (S)-2-aminobutyramide (I) with ethyl 4-bromobutyrate (II) in the presence of triethylamine in toluene gives ethyl (S)-4-[1-(carbamoyl)propylamino]butirate (III), which is cyclized in toluene by means of 2-hydroxypyridine.

合成路线2

Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamol)propyl]-4-chlorobutyramide (V).

合成路线3

Reaction of (S)-2-aminobutyramide (I) with ethyl 4-bromobutyrate (II) in the presence of triethylamine in toluene gives ethyl (S)-4-[1-(carbamoyl)propylamino]butyrate (III), which is cyclized in toluene by means of 2-hydroxypyridine. Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamoyl)propyl]-4-chlorobutyramide (V). An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)butyrate (VI) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane. A third procedure involves Ni-Raney desulfurization of (S)-4-(methylthio)-2-(2-oxopyrrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reaction with 4-chlorobutyryl chloride (IV). Compound (XI) can also be obtained by treatment of (IX) with ethyl 4-bromobutyrate (II) to give ethyl (S)-4-[1-(carbamoyl)-3-(methylthio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.

合成路线4

Reductive amination of 5-hydroxy-4-propyl-2-furanone (I) with (S)-2-aminobutyramide (II) in the presence of NaBH4 yields the dihydropyrrolone (III). Transfer hydrogenation of (III) with ammonium formate and Pd/C provides a diastereoisomeric mixture of pyrrolidinones, from which the title compound is isolated by preparative HPLC on chiral phase.

合成路线5

合成路线6

合成路线7

合成路线8

Condensation of 2(S)-aminobutyramide (I) with Meldrum’s acid derivative (II) in refluxing acetonitrile affords a mixture of two pyrrolidonecarboxylic acid regioisomers, (III) and (IV), which, without isolation, are subjected to decarboxylation in methyl isobutyl ketone at 120 °C, and then separated by column chromatography .
Alternatively, 2(S)-aminobutyramide (I) –obtained by basification of either its tartrate salt with NH4OH/i-PrOH or its hydrochloride salt with NH3/i-PrOH (2)– is reductively condensed with 5-hydroxy-4-propyl-2-furanone (V) by means of NaBH4 and NaOH in H2O/toluene, yielding the dihydropyrrol-2-one (VI) . Transfer hydrogenation of compound (VI) with ammonium formate and Pd/C in H2O at 50 °C provides the diastereomeric mixture of pyrrolidinones (VII) , which are finally separated by column chromatography or recrystallization .
The intermediate dihydropyrrolone (VII) is alternatively obtained by direct condensation of furanone (V) with 2(S)-aminobutyramide (I) in the presence of H2 and Pd/C in AcOH/i-PrOH or by cyclization of aminoamide (I) with 3-(iodomethyl)hexanoyl chloride (VIII) by means of KOH and tetrabutylammonium bromide in CH2Cl2 .
Amide (VII) is also prepared from 2-(2-oxo-4-propylpyrrolidino)-butyric acid (IX) via activation as the corresponding mixed anhydride with ethyl chloroformate and Et3N in THF, followed by quenching with liquid ammonia .
Similarly, alkylation of optically pure 4(R)-propyl-2-pyrrolidinone (X) with racemic methyl 2-bromobutyrate (XI) in the presence of NaH in THF affords pyrrolidinone butyrate methyl ester (XII) as a diastereomeric mixture. Subsequent ammonolysis of ester (XII) with aqueous ammonia gives the corresponding mixture of amides (XIII) separated using column chromatography .