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.
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).
The condensation of 2-pyrrolidone (I) with ethyl 2-bromobutyrate (II) by means of NaOEt in ethanol gives 2-(2-oxopyrrolidin-1-yl)butyric acid ethyl ester (III), which is hydrolyzed with NaOH to the corresponding acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which is treated with ammonia to provide the expected amide (VI). Alternatively, the reaction of acid (IV) with ammonia and thermolysis of the resulting ammonium salt also gives the butyramide (VI). Finally, the optical resolution of the racemic amide (VI) is performed by chiral HPLC.
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.
An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)burytate (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-oxopirrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reacttion 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-(methythio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.
The condensation of pyrrolidin-2-one (I) with ethyl 2-bromobutyrate (II) by means of NaH or sodium ethoxide gives ethyl 2-(2-oxopyrrolidino)butyrate (III), which is then treated with NH3 in methanol.