Patent Watch

September 12, 2011

Enhance the synthesis of a key Alzheimer’s drug precursor. Galantamine (or galanthamine) (1, Figure 1) is an FDA-approved drug for treating mild to moderate cases of Alzheimer's disease and other cognitive disorders. It can be isolated from bulbs and flowers of the snowdrop (Galanthus) and daffodil (Narcissus) families. The molecule is difficult to synthesize because it has three chiral centers.

Despite the patent’s title (“Process for making galantamine”), inventors L. Wang, Y. F. Chen, and J. P. Henschke do not actually describe how to make 1, apart from stating that it can be made from precursor 6. The patent focuses on a process to prepare 6, which can be converted to 7, a key intermediate in the synthesis of 1.

Alternative methods for synthesizing 6 are summarized; one has nine steps, gives a low overall yield, and contains a difficult purification procedure. The inventors report that their process is shorter and relatively inexpensive.

Figure 2 shows the preparation of 6. A key aspect is the use of the bromine atom as a blocking group to prevent attack at the 2-position of the aromatic ring. The process begins with the oxidation of aldehyde 2 to acid 3 with NaOCl in the presence of NH2SO3H. Acid 3 is recovered in 89% yield and is converted to benzoyl chloride 4 through treatment with SOCl2 in the presence of DMF. The claims cover the use of alternative coupling agents to SOCl2 (e.g., N-hydroxy amides) for this step, but the patent does not give any examples.

Benzoyl chloride 4 is recovered as a solution in CH2Cl2 and treated with amine hydrobromide 5 in the presence of NaOH. The free amine is obtained by treating 5 with NaOH before adding the solution of 4. The reaction produces 6, which is purified by heating it to reflux in MeOH with activated carbon. It is then concentrated and dissolved in CH2Cl2.

Adding water precipitates 6; it is recovered and can be used to prepare 7, the intermediate used in the synthesis of 1. There are no details for converting 6 to 7 or for preparing 1, although the formation of 1 from 6 is covered in the claims. The purity and yield of 6 are not reported. The inventors describe two slightly modified methods for preparing 6, but they are smaller-scale experiments with 56–63% yields.

The patent also describes the preparation of 5 by the route outlined in Figure 3. The synthesis begins with treating the alcohol 8 with HBr. After the mixture is heated at 75 °C for 2.5 h, seed crystals of bromide 9 are added and the mixture is kept at this temperature for 24 h. After cooling, 9 is isolated in 96% yield. It is then aminated by adding it to a solution of MeNH2 in i-PrOH. After the reaction is complete, excess MeNH2 is removed, and 5 is isolated in 90% yield.

The preparation of chloro compound 10 is also described; it involves treating 8 with 12 M HCl. The product is obtained in 70% yield.

1H NMR data are reported for all synthesized compounds. The process has fewer steps than its alternatives, and it is likely to be in an advanced stage of development because it has been performed on the kilogram scale. (Scinopharm Taiwan [Tainan County]. US Patent 7,985,879, July 26, 2011; Keith Turner)

What do you think of Patent Watch? Let us know.