Development of a Pilot Scale Process for the Anti-Alzheimer Drug (-)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and Crystallisation-Induced Chiral Conversion

(-)-Galanthamine has been synthesised using an efficient ninestep procedure, which in large scale affords 12.4 (6.7-19.1)% overall yield. The process improvements and optimization of each step are described. Notable steps include (i) an oxidative phenol coupling and (ii) crystallisation-induced chiral conversion of (()-narwedine to (-)-narwedine. This is a practical and cost-effective synthesis of (-)-galanthamine which is amenable to pilot plant scale-up to afford sufficient material for use in clinical trials. Introduction Galanthamine, an Amaryllidaceae alkaloid, has been used clinically for 30 years for treatment of myasthenia gravis1 and other neurological illnesses such as poliomyelitis,2 as an anti-curare agent,3 and as a parasympathomimetic.4 More importantly, it has been approved for the treatment of Alzheimer’s disease in Austria and is in phase III clinical trials both in the United Kingdom and the Unites States.5-6 Galanthamine is produced by isolation from botanical sources (e.g, Galanthus niValis, G. narcissus, G. leucojum, or G. crinium7-9); despite renewed efforts,9 these sources are not suitable for generation of large enough quantities of galanthamine (Figure 1). We had requirements for large quantities of galanthamine for in vitro and in vivo efficacy studies and pharmacokinetic studies. Galanthamine was first synthesised by Barton10 with a pivotal synthetic step being an oxidative phenol cyclization (0.5% yield). Other researchers were able to increase both the yields and the scale of the Barton procedure. Other syntheses of galanthamine have been reported.11-13 While these procedures are workable on a laboratory scale, their scale-up to multi-kilogram scale is operationally prohibitive. We have recently communicated a more efficient route.12 We report herein refinements to our earlier process which allows for large-scale synthesis of galanthamine (Scheme 1). Results and Discussion Step 1: 2-Bromo-4,5-dimethoxybenzaldehyde (1). Bromination of 3,4-dimethoxybenzaldehyde in acetic acid has been reported previously.14 By substituting methanol for acetic acid, we obtained 1 in 90-92% yield. While it has been reported that reaction of bromine with methanol may be vigorously exothermic,15 on the scale indicated in our experimental only a mildly exothermic reaction occurred (temperature increase from room temperature to about 40 °C) when bromine was added with water-cooling. On a 50 g laboratory scale in experiments using the same concentrations as the 4.0 kg experiment, designed to identify potential hazards, bromine was added at once without cooling, resulting in an exotherm, but the reaction temperature never exceeded 45-50 °C. The product contained less than 1% of the 3-bromo-4,5-dimethoxy-benzaldehyde as determined by HPLC and NMR. This procedure has been scaled up to 100 kg quantities with similar yields of 90-92%. Ethanol was less suitable because of decreased solubility and lower yields. Step 2: 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (2) by Regioselective Demethylation of 1. Substituted † Sanochemia AG. ‡ Vienna University of Technology. § E-mail: [email protected]. | E-mail: [email protected]. ⊥ E-mail: [email protected]. (1) Chistoni, G.; Guaraldi, G. P. RiV. Neuropsichiatr. Sci. Affini (Parma) 1960, 6, 53. (2) Göppel, W.; Betram, W. Psychiatr. Neurol. Med. Psychol. 1971, 23, 712. (3) Mayrhofer, O. South. Med. J. 1966, 59, 1364. (4) Baraka, A.; Sami Harik, M. D. JAMA, J. Am. Med. Assoc. 1977, 238, 2293. (5) Mucke, H. A. M. Drugs Future 1997, 33, 259. (6) Rainer, M. Drugs Today 1997, 33, 273. (7) Mikhno, V. V. Farm. Zh. (KieV) 1966, 21, 28. (8) Bastida, J.; Viladomat, F.; Llabres, J. M.; Quiroga, S.; Codina, C.; Rubiralta, M. Planta Med. 1990, 56, 123. (9) Hille, Th.; Hoffmann, H. R.; Kreh, M.; Matusch, R. DE 19,509,663 Lts, Lohmann Therapie-Systeme; Chem. Abstr. 125, 230784 (10) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. 1962, 806. (11) Anonymous, Synform 1983, 283. (12) Czollner, L.; Frantsits, W.; Küenburg, B.; Hedenig, U.; Fröhlich, J.; Jordis, U. Tetrahedron Lett. 1998, 39, 2087. (13) a) Chaplin, D. A.; Fraser, N.; Tiffin, P. D. Tetrahedron Lett. 1997, 38, 7931. The same process was presented in more detail: (b) McCague, R. Complete Industrial Total Synthesis of the Alkaloid (-)-Galanthamine; presented at Chiral USA ‘98, May 18-19, San Francisco, 1998. (14) Pschorr, R. Ann. Chem. 1912, 391, 23. (15) Hazards in the Chemical Laboratory 3rd ed.; Bretherick, L., Ed.; Royal Society of Chemistry:London, 1981; p 99. Figure 1. Structure of (-)-galanthamine, 1; HBr-salt (10): nivalin, reminyl. Organic Process Research & Development 1999, 3, 425−431 10.1021/op990019q CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry Vol. 3, No. 6, 1999 / Organic Process Research & Development • 425 Published on Web 11/04/1999 dimethoxybenzaldehydes can be demethylated regioselectively.16-17 Other methods for the preparation of 2, such as the bromination of isovanilline with bromine18-20 or thionyl bromide21 provided poor regioselectively and/or mediocre yields. Selective 5-O-demethylation of 1 was achieved with concentrated sulfuric acid at 90 °C. Optimal conversion and yield is obtained after 6 h with a 5:1 sulfuric acid/substrate