Synthesis of Anastrozole

Anastrozole (2) and letrozole (3) are type II aromatase inhibitors. They competitively inhibit the conversion of androgens to estrogens. They are both potent and selective aromatase inhibitors. Anastrozole is the most extensively investigated third-generation aromatase inhibitor. It is very potent, with a daily dose of a mere 1 mg. Its safety profile is well developed all doses evaluated up to 10 mg were well tolerated and no serious adverse events were attributed to it. No clinical or laboratory evidence of adrenal insufficiency was observed. 

Anastrozole is well absorbed following oral administration. The maximum plasma concentration of the drug occurs at 2 h from dosing, that is, C ax = 2 h. It is cleared slowly, with a half-life of 30-50 h. The drug is metabolized extensively and only 10% of the drug is excreted in urine as the unchanged drug. 

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The synthesis of anastrozole (Scheme 3.3) began with an 8 2 displacement of commercially available 3,5-fc (bromomethyl)toluene (19) using potassium nitrile and a phase-transfer catalyst, tetrabutylammonium bromide (Edwards and Large, 1990). The resulting fcw-nitrile 20 in DMF was then deprotonated with sodium hydride in the presence of excess methyl iodide to give the fc -dimethylated product 21. Subsequently, a Wohl-Ziegler reaction on 21 was carried out using A-bromosuccinamide (NBS), and a catalytic amount of benzoyl peroxide (BPO) as the radical initiator. Finally, an Sn2 displacement of benzyl bromide 22 with sodium triazole in DMF afforded anastrozole (2) as a white solid. 

Anastrozole is an aromatase inhibitor that is used to treat breast cancer by decreasing the amount of estrogen synthesized by the human body. The synthesis of anastrozole entails a selective bromination and alkylation reaction with 1,2,4-triazole. 

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