Patent EA-001364-B1 (EA)
Title: Stereospecific preparation of chiral 1-aryl- and 1-heteroaryl-2-substituted ethyl-2-amines
Inventor: GRONDARD LUC
IPC: C07C307/00
Filed: 1997-09-10
Abstract: 1. A method for stereospecifically preparing a [(l-optionally substituted aryl)- or (l-optionally substituted heteroaryl)l-2-substituted ethyl-2-amine, having chirality at the 2-posilion, comprising reacting a 2-amino-2-substituted ethyl alcohol, having chirality at the 2-position, with an [(optionally substituted aryl)- or (trihalomethyl) sulfonyl]- halide or anhydride in the presence of a base to form an [(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality at the 2 position. 2. A method according to claim 1 further comprising reacting said aziridine with an [(optionally substituted aryl)- or (optionally substituted heteroaryl)] lithium compound to form the lithium salt of an [(N-optionally substituted aryl)- or (N-trihalomethyl)sulfonyl]-1-[(optionally substituted aryl)- or (optionally substituted heteroaryl)]-2-substituted alkyl-2-amine having chirality at the 2 position. 3. A method according to claim 2 further comprising treating said lithium salt with one or more strong acids in the presence of an electrophilic scavenger. 4. A method according to claim 1 for preparing a compound of formula   wherein * indicates a chiral carbon atom, R1 is optionally substituted aryl, or optionally substituted heteroaryl; and R3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; comprising reacting a compound of formula   with a compound of formula  R2-SO2-R wherein R' is halo or OSO2R2; and R2 is optionally substituted aryl, or trihalomethyl, in the presence of a base to form an aziridine compound of formula   5. A method according to claim 4 further comprising reacting said aziridine compound with compound of formula Li-R1, to form a lithium compound of formula   or an aggregate thereof, wherein R1 is an optionally substituted aryl or an optionally substituted heteroaryl: R2 is an optionally substituted aryl or trihalomethyl; and R3 is an optionally aryl, an optionally aralkyl, an optionally substituted heteroaryl or an optionally substituted heteroaralkyl. 6. A method according to claim 5 further comprising treating said lithium compound with a strong acid or mixture of strong acids in the presence of an electrophilic scavenger. 7. A method according to claim 4 wherein said reacting occurs in an aprolic organic solvent. 8. A method according to claim 7 wherein said aprolic organic solvent is tert-butyl methyl ether. 9. A method according to claim 4 wherein R2-SO2-R' is p-toluenesulfonyl chloride. 10. A method according to claim 4 wherein said reacting occurs at about 25 degree C to about 90 degree C. 11. A method according to claim 4 wherein said reacting occurs at about 25 degree C to about 40 degree C. 12. A method according to claim 4 wherein said base is selected from the group consisting of an aqueous alkali metal hydroxide. an aqueous alkali metal carbonate. and an aprotic organic amine. 13. A method according to claim 4 wherein said base is aqueous sodium hydroxide. 14. A method according to claim 4 wherein R1 is optionally substituted heteroaryl. 15. A method according to claim 14 wherein R1 is 3-chlorothien-2-yl. 16. A method according to claim 4 wherein R3 is alkyl. 17. A method according to claim 16 wherein R3 is ethyl. 18. A method according to claim 5 wherein said reacting said aziridine compound occurs in a solvent selected from the group consisting of an aprotic organic ether, aliphatic hydrocarbon, and an aromatic hydrocarbon. 19. A method according to claim 18 wherein said reacting said aziridine compound occurs in tert-butyl methyl ether. 20. A method according to claim 5 further comprising isolating said lithium compound as a solid. 21. A method according to claim 5 wherein said reacting occurs at about -80 degree C to about 50 degree C. 22. A method according to claim 21 wherein said reacting occurs at about -40 degree C to about 50 degree C. 23. A method according to claim 6 wherein said mixture of strong acids comprises methanesulfonic acid and trifluoroacetic acid. 24. A method according to claim 6 wherein said electrophilic scavenger is thioanisole. 25. A method according to claim 6 wherein said treating occurs at about 45 degree C to about reflux. 26. The [(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)l-2-substituled aziridine having chirality at the 2-position according to claim 1. 27. The aziridine compound according to claim 4 of formula   wherein R2 is an optionally substituted aryl or trihalomethyl; and R3 is an optionally aryl, an optionally aralkyl, an optionally substituted heteroaryl or an optionally substituted heteroaralkyl. 28. A compound according to claim 27 which is 1-p-toluenesulfonyl-2(R)-ethylaziridine. 29. The lithium salt of an [(N-optionally substituted aryl)- or (N-trihalomethyl)sulfonyl] 1-[(optionally -substituted aryl)- or (optionally substituted heteroaryl)]-2-substituted alkyl-2-amine having chirality at the 2-position according to claim 2. 30. The lithium compound according to claim 5 of formula   or an aggregate thereof, R1 is an optionally substituted aryl or an optionally substituted heteroaryl: R2 is an optionally substituted aryl or trihalomethyl; and R3 is an optionally aryl, an optionally aralkyl, an optionally substituted heteroaryl or an optionally substituted heteroaralkyl. 31. A lithium compound according to claim 30 which is (R)-1-(3-chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt.