Anastrozole 1 is an anti-tumor drug for the treatment of breast cancer.

A key step in synthesis of 1 is exhaustive methylation of 3,5-bis(cyanomethyl)toluene 2, whose elegant synthesis from commercially available 5-methylisophthalic acid was described recently¹.

Methylation of 2 was performed using sodium hydride in DMF as a base and methyl iodide² or methyl p-toluenesulphonate¹ as alkylating agents. Application of PTC (phase transfer catalysis, 50%NaOH in the presence of a catalyst - benzyltriethylammonium chloride) for this purpose was patented³, however purity of product obtained precluded its use for synthesis of 1 ⁴. This result is not surprising, because it is well known, that introduction of the second alkyl group to the 2-arylalkane nitriles under PTC conditions proceeds with difficulty.

We found recently, that PTC alkylation of phenylacetonitrile derivatives carried out in the presence of 60-75% aqueous KOH, instead of the typical 50% NaOH, provide substantial improvements in the overall yield and purity of products^5,6.

Application of such system to methylation of 2 (methyl bromide as an alkylating agent, 60% KOH aqueous solution as a base in the presence of 1 molar percent of tetrabutylammonium bromide, toluene as a solvent) resulted in formation of tetramethylated product 3 in high isolated yield 88% and purity exceeding 99% after crystallization from ethanol.

1) Y. Mei, Y. Luo, W. Lu, Org. Prep. Proc. Int., 40, 487 (2008).

2) T. Jackson, L. W. L. Woo, M. N. Trusselle, S. K. Chander, A. Purohit, M. J. Reed, B. V. L. Potter, Org. Biomol. Chem., 5, 2940 (2007).

3) O. Achmatowicz, W. Pucko, E. Chojecka-Koryn, G. Grynkiewicz, W. Szelejewski, J. Zagrodzka, G. Cieplucha, Pat. PL 197 935 (2006).

4) E. Chojecka-Koryn, B. Zagrodzki, Przem. Chem., 85, 338 (2006).

5) M. Barbasiewicz, K. Marciniak, M. Fedoryński, Tetrahedron Lett., 47, 3871 (2006).

6) M. Fedoryński, M. Jezierska-Zięba, B. Kąkol, Przem. Chem., 88, 872 (2009).

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