Dynamic diastereomeric salt resolution narwedine and its transformation to (-)-galanthamine

Tetrahedron Letters

Volumn 39, Issue 37, 1998, Pages 6777-6780

  Chaplin, David A ^a   Johnson, Nicholas B ^a   Paul, Jane M ^a   Potter, Gerard A ^a,b  

^a Chiroscience Ltd   (United Kingdom)

^b DE MONTFORT UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GALANTAMINE;

ALZHEIMER DISEASE; ARTICLE; CRYSTALLIZATION; DRUG SYNTHESIS; METHODOLOGY; NONHUMAN; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

EID: 0032505214     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)01424-5     Document Type: Article

References (17)

1. 2. Rainer, M. CNS Drugs, 1997, 7, 89.
2. 3. Barton, D.H.R. and. Kirby G.W. Proceedings, 1960, 392.
3. 4. Barton, D.H.R. and. Kirby G.W. J. Chem. Soc., 1962, 806.
4. 5. Shieh, W-O. and Carlson, J. A. J. Org. Chem., 1994, 59, 5463.
5. 6. Shieh, W-O. and Carlson, J. A. WO 95/27715 (Ciba Geigy).
6. 7. Henshilwood, J. and Johnson, N. B. WO 96/31458 (Chiroscience).
7. 8. Dyer, U., Paul, J. M. and McCague, R. WO 96/31453 (Chiroscience).
8. 9. Chaplin, D.A.; Fraser, N. and Tiffin, P.D. WO 97/11077 (Chiroscience).
9. 10. Chaplin, D. A., Johnson, N. B., Paul, J. M. and Potter, G. A. WO 975431 (Chiroscience).
10. 11. Chaplin, D. A.; Fraser, N. and Tiffin, P. D. Tetrahedron Lett., 1997, 38, 7931.
11. 12. Narwedine was prepared synthetically by the process described in references 7 and 11.
12. 13. Due to the base mediated racemisation of narwedine the salt was not cracked to liberate free narwedine for e.e. assay. A solution of the salt was directly injected onto the HPLC column where it dissociated in-situ and the e.e. of narwedine within the salt was obtained. Acetic acid was added to the to prevent racemisation of narwedine on the column. HPLC conditions: Chirocel OD. Size 25 cm × 4.6 mm. Particle size 10μm. 49.5% heptane, 49.5% ethanol and 1% acetic acid. 1 ml/min. 5 °C. 210 nm. (-)-Narwedine (6.20 minutes), (+)-narwedine (10.20 minutes).
13. 14. General procedure for preparation of the 1:1 salt and 2:1 salt: Racemic narwedine was dissolved in ethanol (10 volumes) on warming. Di-p-toluoyl-D-tartaric acid (1.0 mol equivalent for the 1:1 salt and 0.5 mol equivalent for the 2:1 salt) was added to the hot solution. The mixture was heated at reflux for 1 h and then slowly cooled to 40 °C and maintained at this temperature for 16 hours. The mixture was then cooled to ambient temperature and the crystals were isolated by filtration and washed with ethanol and ether to afford the 1:1 salt or 2:1 salt respectively.
14. 15. Eliel, E. L., Wilen, S. H. and Mander, L. N. 'Stereochemistry of Organic Compounds', John Wiley and Sons Inc., 1994, Chapter 7, pages 311-314 and references therein.
15. 16. Epigalanthamine is the epimer at C-OH relative to galanthamine.
16. 17. Szewczyk, J., Lewin, A. and Carrol, F. I. J. Heterocyclic Chem., 1988, 25, 1809. This result was repeated in our labs.
17. 4), and evaporated to afford (-)-galanthamine. HPLC conditions: Chirocel OD. Size 25 cm × 4.6 mm. Particle size 10μm., 95:5 heptane:ethanol. 1 ml/min. 5 °C. 210 nm. (-)-Galanthamine (57.0 minutes), (+)-galanthamine (70.10 minutes).