Claims
- 1. A process for the resolution of one desired (1R,4S) or (1S,4R) isomer of (.+-.)-1-azabicyclo[2.2.1]heptan-3-one, said process comprising:
- a) dissolving a mixture of (1R,4S)- and (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one in a selective crystallization-effective solvent comprising one or more protic and/or aprotic solvents to form a separable mixture;
- b) combining with said separable mixture a di-p-toluoyltartaric acid isomer such that substantially one but not both of the following pairs of compounds will be present in said separable mixture:
- b)I) (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-L-tartaric acid; or
- b)ii) (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-d-tartaric acid;
- c) allowing a precipitate to form and collecting said solid precipitate from the mother liquid of said separable mixture, said precipitate comprising:
- c)I) (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid hemisalt; or
- c)ii) (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-D-tartaric acid hemisalt;
- wherein a precipitate comprising c)I) is obtained when said separable mixture comprises b)I) and
- wherein a precipitate comprising c)ii) is obtained when said separable mixture comprises b)ii).
- 2. The process of claim 1 wherein said one desired isomer is (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, said di-p-toluoyltartaric acid is di-p-toluoyl-L-tartaric acid, and said precipitate comprises (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid hemisalt.
- 3. The process of claim 1 wherein said one desired isomer is (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, said di-p-toluoyltartaric acid is di-p-toluoyl-D-tartaric acid, and said precipitate comprises (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-D-tartaric acid hemisalt.
- 4. The process of claim 2 wherein said di-p-toluoyl-L-tartaric acid is combined with said separable mixture in an amount of from about 50% to about 100% of stoichiometry calculated as the hemisalt from the amount of (1S,4R) isomer contained in said separable mixture.
- 5. The process of claim 2 wherein said di-p-toluoyl-L-tartaric acid is combined with said separable mixture in an amount of from about 70% to about 90% of stoichiometry calculated as the hemisalt from the amount of (1S,4R) isomer contained in said separable mixture.
- 6. The process of claim 3 wherein said di-p-toluoyl-D-tartaric acid is combined with said separable mixture in an amount of from about 50% to about 100% of stoichiometry calculated as the hemisalt from the amount of (1R,4S) isomer contained in said separable mixture.
- 7. The process of claim 3 wherein said di-p-toluoyl-D-tartaric acid is combined with said separable mixture in an amount of from about 70% to about 90% of stoichiometry calculated as the hemisalt from the amount of (1R,4S) isomer contained in said separable mixture.
- 8. The process of claim 1 wherein said selective crystallization solvent comprises one or more of alcohol solvents, ether solvents, ester solvents, and nitrile solvents.
- 9. The process of claim 1 wherein said selective crystallization solvent is selected from the group consisting of acetonitrile, ethyl acetate and isopropyl alcohol.
- 10. A process for the resolution of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, said process comprising:
- a) dissolving a mixture of (1R,4S)- and (1S,4R)-a-azabicyclo[2.2.1]heptan-3-one in a selective crystallization--effective solvent comprising one or more protic and/or aprotic solvents to form a separable mixture;
- b) combining with said separable mixture, di-p-toluoyl-L-tartaric acid;
- c) allowing a precipitate to form and collecting said solid precipitate from the mother liquid of said separable mixture, said precipitate comprising (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid hemisalt.
- 11. The process of claim 10 wherein said di-p-toluoyl-L-tartaric acid is combined with said separable mixture in an amount of from about 50% to about 100% of stoichiometry calculated as the hemisalt from the amount of (1S,4R) isomer contained in said separable mixture.
- 12. The process of claim 10 wherein said di-p-toluoyl-L-tartaric acid is combined with said separable mixture in an amount of from about 70% to about 90% of stoichiometry calculated as the hemisalt from the amount of (1S,4R) isomer contained in said separable mixture.
- 13. A process for the resolution of one (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, said process comprising:
- a) dissolving a mixture of (1R,4S)- and (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one in a selective crystallization--effective solvent comprising one or more protic and/or aprotic solvents to form a separable mixture;
- b) combining with said separable mixture di-p-toluoyl-d-tartaric acid;
- c) allowing a precipitate to form and collecting said solid precipitate from the mother liquid of said separable mixture, said precipitate comprising (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-D-tartaric acid hemisalt.
- 14. The process of claim 13 wherein said di-p-toluoyl-D-tartaric acid is combined with said separable mixture in an amount of from about 50% to about 100% of stoichiometry calculated as the hemisalt from the amount of (1R,4S) isomer contained in said separable mixture.
- 15. The process of claim 13 wherein said di-p-toluoyl-D-tartaric acid is combined with said separable mixture in an amount of from about 70% to about 90% of stoichiometry calculated as the hemisalt from the amount of (1R,4S) isomer contained in said separable mixture.
- 16. A composition comprising the compound: ##STR5##
- 17. A composition comprising the compound:
- 18. A composition comprising a hydrate, solvate or mixture thereof of the compound of claim 16.
- 19. A composition comprising a hydrate, solvate or mixture thereof of the compound of claim 17.
Parent Case Info
This application is a 371 of PCT/US98/01413 filed Jan. 27, 1998, and is based on provisional application No. 60/036,285 filed Jan. 27, 1997.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US98/01413 |
1/27/1998 |
|
|
9/29/1999 |
9/29/1999 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO98/32759 |
7/30/1998 |
|
|
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5346911 |
Augelli-Szafran et al. |
Sep 1994 |
|
Non-Patent Literature Citations (2)
Entry |
Boelsterli et al., "39. Absolute Configuration of 3-Substituted 1-Azabicyclo[2.2.1]heptanes," Helvetica Chimica Acta, vol. 75, pp. 507-512, 1992. |
Jerry March, Advanced Organic Chemistry, Fourth Edition, p. 108, 1992. |