Patent Watch

February 21, 2011

Here is a new route to an important anti-emetic drug. Dolasetron (14), available commercially as Anzement, is used as an anti-emetic that is especially useful to chemotherapy patients. Inventors J. A. P. Andres, P. D. Barjoan, and J. H. Clotet summarize several alternative processes for preparing 14 and state that all of them have shortcomings (e.g., the use of protecting groups or column chromatography) that make them unsuitable for commercial production. They disclose that novel esters 5 (R = Et or Me) are particularly useful in the synthesis of 14. These compounds and their synthesis are the subject of the patent and its claims.

The first sequence in the figure outlines the synthesis of 5 via the formation of 3 and 4. In the case of R = Et, the first step is the base catalyzed condensation of 1 with 2 to form 3 as a colorless oil in 75% yield after evaporating DMF, extracting into toluene, and washing in water. Further condensation of 2 with 3 produces 4, also recovered as an oil in 70% yield. In the final step, 4 is decarboxylated by heating it with NaBr in DMF, and 5 is isolated in 80% yield as a colorless oil. For R = Me, 5 is prepared in a one-pot process without isolating intermediate 3.

The preparation of 14 from 5 (R = Me) requires several stages. The HCl salt of 9 is formed in the first stage as shown in the second sequence. Acid hydrolysis of 5 forms 6, which is not isolated but undergoes a Robinson–Schöpf condensation with 7 and 8 in the presence of Na2HPO4 to produce 9. The free base can be isolated by evaporating the solvent; alternatively, the HCl salt is obtained as a monohydrate after being crystallized from i-PrOH–H2O. X-ray diffraction and IR data for polymorph form I of this salt are given. The inventors describe this salt as a key aspect of the patent.

The next stage in the synthesis of 14 is shown in the third sequence; 9 is reduced with NaBH4 to give 10 in 76% isolated yield as a colorless oil. Esterification of 10 with 11 uses (CF3CO)2 and a catalytic amount of 4-dimethylaminopyridine to produce 12. This is isolated in 89% yield after being filtered and dried. It is used directly in the fourth sequence, or it can be converted to its HCl salt.

In the last stage, treating 12 with t-BuOK in a Dieckmann reaction forms 13. Heating with LiCl in DMF produces 14 by dealkoxycarboxylation. The free base is isolated in 83% yield and can be purified by methods previously reported (Anzeveno, P. B. Eur. Pat. EP0339669 [1989]).

1H NMR, 13C NMR, and IR data are given for all of the ethoxy and methoxy intermediates and final products. The patent provides a route to dolasetron that is the inventors claim is commercially viable. (INKE SA [Barcelona, Spain]. US Patent 7,858,821, Dec. 28, 2010; Keith Turner)

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