Patent Watch

August 5, 2013

Make a potential cancer drug in high yield and fewer steps. 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoymethyl)piperidin-4-yl]oxy}quinazoline (compound 3), is under investigation as a breast cancer drug. K. A. Boardman and co-inventors describe high-yield preparation methods that contain fewer reaction steps than earlier methods.

The inventors developed two seven-step methods for synthesizing compound 3. Figure 1 shows the last step of each route. In the first route, precursors 1 and 2 react in the presence of HOAc to give 3 in 55% isolated yield. In the second, compounds 4 and 5 react under similar conditions to give a 95% isolated yield of 3.

Three routes to potential cancer drug 3

These two reactions form the basis of the patent’s claims. The inventors do not state the purity of the products, but 1H NMR and X-ray diffraction data are given. The difumarate salt of compound 3 can be prepared from 4 and 5 by running the reaction in t-BuOH in the presence of fumaric acid; the salt is isolated in 61.4% yield.

Compound 3 can also be formed by the reaction of 4 with formamidine 6 in the presence of HOAc. The product is isolated in 73% yield. 1H NMR, however, indicates the presence of the anisole solvent and residual water.

The preparation of the starting materials used in these reactions is shown in Figure 2. The synthesis of 4 begins with the reaction of tert-butoxycarbonyl (Boc)–protected amine 7 with functionalized phenol 8 in the presence of K2CO3 to produce 9, which is recovered by crystallization in 80% isolated yield. The Boc group in 9 is removed with HCl–EtOH, and 10 is isolated as the HCl salt in 77% yield. In the next step, 10 is treated with chloroacetamide (11) in the presence of K2CO3 to give 12 in 94% yield; 12 is then nitrated to give 13. The nitro compound is isolated in 82% yield and reduced with Na2S2O4 to give 4 in 78%isolated yield.

Synthesis of intermediates 3 and 4

Starting compound 1 is prepared by treating 4 with acetal 14 in HOAc. The product is obtained in 97% yield after crystallization. The inventors also report syntheses of compounds 5 and 6 from 2.

The final aspect of the patent is the preparation of a polymorph of the difumarate salt of 3. Examples describe the preparation of this salt on a kilogram scale, indicating the advanced stage of commercialization of the process. The salt may be obtained from 3 by treating it with fumaric acid in i-PrOH, MeOH–i-PrOH, or EtOAc–i-PrOH. The X-ray diffraction pattern of the salt is provided.

Several of the intermediates produced in the routes to 3 are novel. The inventors provide 1H NMR data for all of these, but unfortunately they do not report the purity of any reaction product. Despite this, the inventors claim that the process provides a route to 3 that contains minimal impurities.

In summary, the processes provide routes to the desired compound in fewer steps than alternatives and are suitable for large-scale production. (AstraZeneca AB [Sodertälje, Sweden]. US Patent 8,450,482, May 28, 2013; Keith Turner)

View patent information from CAplus(SM) database.

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