Patent EA-002438-B1 (EA)
Title: Process for preparing 2-azadihydroxybicyclo[2.2.1]heptane compounds and the l-tartaric acid salt of the compound
Inventor: O'BRIEN MICHAEL
IPC: C07D209/02
Filed: 1997-10-15
Abstract: 1. A method for the preparation of a 2-azadihydroxybicyclo [2.2.l]heptane derivative of formula:   wherein * represents an R-chirality, *' represents an S-chirality, R is hydrogen or, respectively, a group of formula   wherein R1 is C1-C4alkyl and Ar is phenyl or α-naphthyl, or β-naphthyl, which can be optionally substituted by one or more substituents such as halo, C1-C4alkyl, C1-C4alkoxy or nitro, comprising bishydroxylating a bicyclo[2.2.1]heptene derivative of formula   in the presence of about 0.1 mol % to about 5 mol % of a metal osmate compound or about 0.06 mol % to about 0.07 mol % osmium tetroxide, and an oxidizing agent capable of regenerating osmium tetroxide. 2. The method according to Claim 1 wherein R is the group of formula   3. The method according to Claim 2 wherein R1 is methyl or ethyl and Ar is optionally substituted phenyl, which when is substituted then it is substituted with one or more methyl or methoxy. 4. The method according to Claim 3 wherein R1 is methyl, and Ar is phenyl. 5. The method according to Claim 1 wherein the bishydroxylation is effected using osmium tetroxide at about 0.06 mol % to about 0.07 mol %. 6. The method according to Claim 5 wherein the osmium tetroxide is present at about 0.06 mol %. 7. The method according to Claim 1 wherein the bishydroxylation is effected using metal osmate at about 0.1 mol % to about 5 mol %. 8. The method according to Claim 7 wherein the metal osmate is present at about 0.2 to about 0.5 mol %. 9. The method according to Claim 1 wherein the metal osmate is K2OsO4.2H2O. 10. The method according to Claim 1 wherein the oxidizing agent capable of regenerating osmium tetroxide is N-methylmorpholine oxide. 11. A method for the preparation of an L-tartaric acid salt of the (1R) diastereomer of the 2-azadihydroxybicyclo[2.2.1]heptane compound according to Claim 1, comprising treating with L-tartaric acid (1R) diastereomer derivative of the 2-azadihydroxybicyclo[2.2.1]heptane according to Claim 1 wherein R is a group of formula   wherein R1 is C1-C4alkyl and Ar is phenyl or α-naphthyl, or β-naphthyl, which can be optionally substituted by one or more substituents such as halo, C1-C4alkyl, C1-C4alkoxy or nitro. 12. The method according to Claim 11 wherein R1 is methyl and Ar is phenyl. 13. The method according to Claim 11 further comprising preparing the L-tartaric acid salt of the (1R) diastereomer of the 2-azadihydroxybicyclo[2.2.1]-heptane derivative in a substantially enantiomerically purified state in the presence of a (1S) diastereomer of the 2-azadihydroxybicyclo [2.2.1 ]heptane derivative. 14. The method according to Claim 11 wherein the treating occurs in an aqueous-organic solvent mixture. 15. The method according to Claim 14 wherein organic solvent is isopropanol. 16. The method according to Claim 14 wherein the treating occurs in an aqueous-isopropanol solvent mixture having a volume ratio of about 30:70 to about 15:85. 17. The method according to Claim 16 wherein the volume ratio is about 25:75. 18. The compound of formula   wherein R is as defined in Claim 11.