Process for the preparation of enantiomers of amidoacetonitrile compounds from their racemates

1. A method of preparation of a single enantiomer from the racemate of an amidoacetonitrile compound of formula

wherein

R 1 , R 2 and R 3 , independently of each other, signify hydrogen, halogen, nitro, cyano, C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen-C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, halogen-C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, halogen-C 2 -C 6 -alkinyl, C 2 -C 6 -alkenyloxy, halogen-C 2 -C 6 -alkenyloxy, C 1 -C 6 -alkylthio, halogen-C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfonyloxy, halogen-C 1 -C 6 -alkylsulfonyloxy, C 1 -C 6 -alkylsulfinyl, halogen-C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, halogen-C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -alkenylthio, halogen-C 1 -C 6 -alkenylthio, C 1 -C 6 -alkenylsulfinyl, halogen-C 1 -C 6 -alkenylsulfinyl, C 1 -C 6 -alkenylsulfonyl, halogen-C 1 -C 6 -alkenylsulfonyl, C 1 -C 6 -alkylamino, di-(C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylaminocarbonyl, di-(C 1 -C 6 -alkyl)aminocarbonyl, C 1 -C 6 -alkylsulfonylamino, halogen-C 1 -C 6 -alkylsulfonylamino, C 1 -C 6 -alkylcarbonyl, halogen-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, unsubstituted or one- to five-fold substituted phenyl, unsubstituted or one- to five-fold substituted phenoxy, unsubstituted or one- to five-fold substituted phenylacetylenyl, unsubstituted or one- to four-fold substituted pyridyloxy, unsubstituted or one- to four-fold substituted pyridyl or unsubstituted or one- to seven-fold substituted naphthyl, the substituents in each case being selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and halogen-C 1 -C 6 -alkoxy,

characterized in that

1) the racemate is separated into two pure enantiomers by standard methods and the eutomer is collected,

2) the distomer is re-racemized using basic catalysis and/or heating in a polar solvent, and

3) the resulting racemate is again subjected to the separation procedure of step 1) in a repetitive cycle.

2. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify halogen, C 1 -C 6 halogenalkyl or CN.

3. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify C 1 -C 4 halogenalkyl or CN.

4. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify halogenmethyl or CN.

5. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify trifluoromethyl or CN.

6. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 3 signifies halogen-C 1 -C 6 -alkoxy, halogen-C 1 -C 6 -alkylsulfonyl, halogen-C 1 -C 6 -alkylsulfinyl or halogen-C 1 -C 6 -alkylthio.

7. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 3 signifies halogen-C 1 -C 2 -alkoxy, halogen-C 1 -C 2 -alkylsulfonyl, halogen-C 1 -C 2 -alkylsulfinyl or halogen-C 1 -C 2 -alkylthio.

8. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 3 signifies halogenmethoxy, halogenmethylsulfonyl, halogenmethylsulfinyl or halogenmethylthio.

9. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 3 signifies trifluoromethoxy, trifluoromethylsulfonyl, trifluoromethylsulfinyl or trifluoromethylthio.

10. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify halogen, C 1 -C 6 halogenalkyl or CN; and R 3 signifies halogen-C 1 -C 6 -alkoxy, halogen-C 1 -C 6 -alkylsulfonyl, halogen-C 1 -C 6 -alkylsulfinyl or halogen-C 1 -C 6 -alkylthio.

11. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify C 1 -C 4 halogenalkyl or CN; and R 3 signifies halogen-C 1 -C 2 -alkoxy, halogen-C 1 -C 2 -alkylsulfonyl, halogen-C 1 -C 2 -alkylsulfinyl or halogen-C 1 -C 2 -alkylthio.

12. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify halogenmethyl or CN; and R 3 signifies halogenmethoxy, halogenmethylsulfonyl, halogenmethylsulfinyl or halogenmethylthio.

13. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , wherein R 1 and R 2 , independently of each other, signify trifluoromethyl or CN; and R 3 signifies trifluoromethoxy, trifluoromethylsulfonyl, trifluoromethylsulfinyl or trifluoromethylthio.

14. A method of preparation of a single enantiomer from the racemate of N-(1-cyano-2-(5-cyano-2-trifluoromethyl-phenoxy)-1-methyl-ethyl)-4-trifluoromethylsulfanyl benzamide according to claim 1 .

15. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the separation of the enantiomers is carried out by chromatography on a chiral adsorbent.

16. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the chromatographical separation is carried out on a chiral polysaccharide as the stationary phase with an alcohol as the mobile phase.

17. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the chromatographical separation is carried out with a mixture of methanol and alcohol as the mobile phase.

18. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the re-racemization reaction of the distomer is carried out in an ether.

19. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 characterized in that the re-racemization reaction of the distomer is carried out in tetrahydrofuran or dioxane.

20. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the re-racemization reaction of the distomer is carried out in dioxane.

21. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the re-racemization reaction of the distomer is carried out in the presence of sodium cyanide, sodium bicarbonate, sodium carbonate, sodium hydride, potassium carbonate or potassium tert.-butanolate.

22. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the re-racemization reaction of the distomer is carried out in the presence of sodium cyanide.

23. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the re-racemization reaction of the distomer is carried out in a temperature range of about 80° C. to about 120° C.

24. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the re-racemization reaction of the distomer is carried out at about 101° C.

25. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the separation of the enantiomers is carried out by chromatography on a chiral adsorbent and the re-racemization reaction of the distomer is carried out in an ether and in the presence of sodium cyanide, sodium bicarbonate, sodium carbonate, sodium hydride, potassium carbonate or potassium tert.-butanolate in a temperature range of about 80° C. to about 120° C.

26. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the chromatographical separation is carried out on a chiral polysaccharide as the stationary phase with an alcohol as the mobile phase and the re-racemization reaction of the distomer is carried out in tetrahydrofuran or dioxane and in the presence of sodium cyanide at about 101° C.

27. A method of preparation of a single enantiomer from the racemate of a compound of formula I according to claim 1 , characterized in that the chromatographical separation is carried out on a chiral polysaccharide as the stationary phase with a mixture of methanol and alcohol as the mobile phase and the re-racemization reaction of the distomer is carried out in dioxane and in the presence of sodium cyanide at about 101° C.

28. A method of preparation of a single enantiomer from the racemate of N-(1-cyano-2-(5-cyano-2-trifluoromethyl-phenoxy)-1-methyl-ethyl)-4-trifluoromethylsulfanyl benzamide according to claim 14 , characterized in that the chromatographical separation is carried out on a chiral polysaccharide as the stationary phase with a mixture of methanol and alcohol as the mobile phase and the re-racemization reaction of the distomer is carried out in dioxane and in the presence of sodium cyanide at about 101° C.

29. A method of preparation of (−)-(R)-N-(1-cyano-2-(5-cyano-2-trifluoromethyl-phenoxy)-1-methyl-ethyl)-4-trifluoromethylsulfanyl benzamide from the racemate according to claim 28 .