Process for preparing 2-oxo-1-pyrrolidine derivatives by intramolecular allylation

1. A process for the preparation of compounds of general formula (I)

wherein

R 2 and R 3 are the same or different and each is, independently, hydrogen, C 1-4 alkyl, cyano, aryl, —COOR 7 , halogen, R 8 COO—, R 9 SO 3 O— or R 10 SO 2 O—;

R 1 is R a , R b or C 2-20 alkenyl optionally substituted by aryl;

X is —CONR 11 R 12 , —COOR 13 or —CN;

R 7 , R 8 , R 9 and R 10 are each independently chosen from hydrogen, R a′ and R b′ ;

R 11 , R 12 and R 13 are the same or different and each is, independently, hydrogen, C 1-4 alkyl, aryl, arylalkyl, heteroaryl or heterocycloalkyl;

R a and R a′ each independently represent C 1-20 alkyl or C 1-20 alkyl substituted by one or more halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, carboxy, sulfonic acid, R b , alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, acyl, ester, amido, azido, acyloxy, esteroxy and/or amidooxy;

R b and R b′ each independently represent aryl, heterocycloalkyl, heteroaryl or the same substituted by one or more halogen, R a , hydroxy, thiol, amino, nitro, cyano, thiocyanato, carboxy, sulfonic acid, aryl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, heterocycloalkyl, heteroaryl, acyl, ester, amido, azido, acyloxy, esteroxy and/or amidooxy;

comprising the cyclisation of an intermediate of general formula (II)

wherein

Y is a leaving group selected from halogen, —OC(O)R 14 , —OSO 2 —R 15 and —OClO 3 ;

R 14 and R 15 represent halogen or alkyl, arylalkyl, aryl, each optionally substituted by one or more halogen, alkyl, nitro and/or tertiary amino group;

X 1 is as defined for X;

W is an electron withdrawing group selected from —COOR 4 , —COMe, —CN, —PO(OEt) 2 , —SO 2 aryl, —COaryl;

R 4 represents hydrogen, C 1-6 alkyl, aryl, arylalkyl, wherein each aryl and arylalkyl may be substituted by one or more halogen, nitro, and/or methoxy;

in the presence of one or more organic and/or inorganic bases.

2. The process according to claim 1 , wherein Y is halogen, —OC(O)R 14 , —OSO 2 —C 6 H 4 —CH 3 , —OSO 2 —C 6 H 4 —Br, —OSO 2 —C 6 H 4 —NO 2 , —OSO 2 —CH 3 , —OSO 2 —CF 3 , —OSO 2 —C 4 F 9 , —OSO 2 —CH 2 —CF 3 , —OSO 2 —(CH 2 ) n —N + Me 3 , —OSO 2 —F or —OClO 3 .

3. The process according to claim 1 , wherein the base is selected from 1,1,3,3-tetramethylguanidine, sparteine, 1,5,7-triazabicyclo(4.4.0)dec-5-ene, bis(trimethylsilyl)acetamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, tert-butylimino-tri(pyrrolidino)phosphorane, 1,5-diazabicyclo(4.3.0)non-5-ene, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaH or tert-BuOK, optionally in the presence of a phase transfer catalyst.

4. The process according to claim 1 , comprising the hydrolysis of an intermediate of general formula (VII a)

wherein

R 4a is a C 1-6 alkyl;

X 1 is as defined for X is claim 1 ;

R 1 , R 2 and R 3 are as defined in claim 1 .

5. The process according to claim 1 , comprising the decarbalkoxylation of an intermediate of formula (VIIa) as defined in claim 4 or comprising the decarboxylation of an intermediate of general formula (VII b),

wherein

X 2 is as defined for X in claim 1 ;

R 1 , R 2 and R 3 are as defined in claim 1 .

6. The process according to claim 1 , wherein the intermediate of formula (II) is obtained by a method comprising the reaction of an intermediate of formula (III)

wherein

X 3 is as defined for X in claim 1 ;

Y, R 1 , R 2 and R 3 are as defined in claim 1 ;

with a compound of formula (IV)

wherein

R 5 is methoxy, ethoxy, chlorine, hydroxy, —ONa or —OK;

W 1 is as defined for W in claim 1 .

7. The process according to claim 6 , wherein W 1 represents a group of formula —COOR 4b , wherein R 4b represents a C 1-6 alkyl.

8. The process according to claim 6 , wherein intermediate (III) is obtained by a method comprising the reaction of a compound of formula (V)

wherein Y, R 2 and R 3 are as defined in claim 1 and R 6 is a leaving group such as defined for Y in claim 1 ;

with a compound of formula (VI);

wherein X 4 is as defined for X in claim 1 and R 1 is as defined in claim 1 .

9. The process according to claim 8 , wherein R 6 is —OSO 2 —C 6 H 4 —CH 3 .

10. The process according to claim 1 , comprising a step of separation of one or more of the different diastereoisomers of any of the compounds of formula (I), (VIIa) and (VIIb).

11. The process according to claim 1 , wherein the carbon atom indicated by (1*) is in the (S)-form.

12. The process according to claim 1 , wherein the carbon atom indicated by (2*) is in the (S)-form.

13. The process according to claim 5 , comprising a step of isolation of the compound of formula (VII b) wherein the carbon atom indicated by (2*) is in the (S)-form.

14. The process according to claim 1 , wherein W represents a group of formula —COOR 4 .

15. The process according to claim 14 , wherein R 4 represents a C 1-6 alkyl.

16. The process according to claim 1 , wherein R 1 is a C 1-6 alkyl.

17. The process according to claim 16 , wherein R 1 is ethyl.

18. The process according to claim 1 , wherein X, X 1 , X 2 , X 3 and X 4 are —CONR 11 R 12 .

19. The process according to claim 18 , wherein X, X 1 , X 2 , X 3 and X 4 are —CONH 2 .

20. The process according to claim 1 , wherein R 2 and R 3 are halogens.

21. The process according to claim 20 , wherein R 2 and R 3 are fluorine.

22. The process according to claim 1 , wherein Y is halogen.

23. The process according to claim 22 , wherein Y is fluorine.

24. The process according to claim 1 , wherein the compound of formula (I) is (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide.

25. Synthesis intermediates of formula (II a), (III), (VII a), (VII b) and salts thereof

wherein

X 1 , X 2 and X 3 are independently as defined for X in claim 1 ;

R 1 , R 2 , R 3 , R 4 and Y are as defined in claim 1 ;

and R 4a is as defined in claim 4 .

26. Synthesis intermediates according to claim 25 wherein R 1 is ethyl, X 1 , X 2 and X 3 are —CONH 2 ; R 2 , R 3 and Y are F; R 4 and R 4a are methyl or ethyl.

27. Synthesis intermediates according to claim 25 , wherein the carbon atom indicated by (1*) is in the (S)-form.

28. Synthesis intermediate of formula (VII b) according to claim 26 , wherein the carbon atom indicated by (2*) is in the (S)-form.