Process for the preparation of 2-oxo-1-pyrrolidine derivatives

1. A process for the preparation of a compound of formula (I),

wherein the compound of formula (I) is substantially diastereoisomerically pure with respect to stereogenic centers 1* and 2*, and

R 1 is C 1-10 alkyl or C 2-6 alkenyl

R 2 is C 1-10 alkyl or C 2-6 alkenyl,

X is —CONR 4 R 5 , —COOH, —COOR 3 or —CN,

R 3 is C 1-10 alkyl;

R 4 is hydrogen or C 1-10 alkyl;

R 5 is hydrogen or C 1-10 alkyl;

which process comprises

(a) reacting a substantially optically pure compound of formula (II),

wherein

X 1 is —CONR 4 R 5 , —COOH, —COOR 3 or —CN

Y is a leaving group selected from halogen, sulfonate group or —N 2 + ,

with a compound of formula (IV) substantially optically pure at stereogenic center 3*, or salts thereof,

wherein X 2 is —CONR 4 R 5 , —COOH, —COOR 3 or —CN;

in a solvent selected from methanol, isopropanol, tert-butanol, dimethoxyethane, dimethylsulfoxide, dichloromethane, acetonitrile, toluene, and mixtures thereof and in the presence of a base selected from potassium hydride, sodium hydride, sodium methoxide, potassium methoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, triethylamine, cesium carbonate, and triisopropylamine; and

(b) converting the reaction product of II and IV into the compound of the formula I.

2. The process according to claim 1 wherein R 1 is C 1-4 alkyl or C 2-4 alkenyl.

3. The process according to claim 1 wherein R 2 is C 1-4 alkyl.

4. The process according to claim 1 wherein X and X 1 are —CONR 4 R 5 .

5. The process according to claim 1 wherein Y is a halogen or a sulfonate group.

6. The process according to claim 1 wherein the conversion of the reaction product of II and IV into the compound of formula I comprises cyclization of a compound of formula (VI),

wherein

R 1 is hydrogen, C 1-10 alkyl or C 2-6 alkenyl;

R 2 is C 1-10 alkyl or C 2-6 alkenyl;

X 1 is —CONR 4 R 5 , —COOH, —COOR 3 or —CN;

X 2 is —CONR 4 R 5 , —COOH, —COOR 3 or —CN;

R 3 is C 1-10 alkyl.

7. The process according to claim 1 wherein when X=CONH 2 and X 1 is COOR 3 or COOH, the conversion of the reaction product of II and IV into the compound of formula I comprises ammonolysis of a compound of formula (V),

wherein

R 1 is C 1-10 alkyl or C 2-6 alkenyl;

R 2 is C 1-10 alkyl or C 2-6 alkenyl;

X 1 is COOR 3 or COOH; and

R 3 is C 1-10 alkyl;

in the presence of water.

8. The process according to claim 1 wherein

R 1 is n-propyl or 2,2-difluorovinyl;

R 2 is ethyl;

X is —CONH 2 ;

X 1 and X 2 are —CONH 2 , COOH or COOMe; and

Y is bromine, methanesulfonate or trifluoromethanesulfonate.

9. The process according to claim 1 wherein compound of formula (I) is brivaracetam.

10. The process according to claim 1 wherein compound of formula (I) is seletracetam.