1,4-Dioxane → Crizotinib acetate

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Reaction Steps

To a solution of 4—(4—{6—amino—5—[(R)—1—(2,6—dichloro—3—fluoro—phenyl)—ethoxy]—pyridin—3—yl}—pyrazol—1—yl)—piperidine—1—carboxylic acid tert—butyl ester (566.7 mg, 1.03 mmol) in methanol (5 mL) or dichlorometha[pi]e (30 mL) was added 4N HCI/dioxane (15 mL). The solution was stirred for about 1 hour or until the de-protection was complete. The solvents were evaporated and the residue was dissolved in methanol and purified on a reversed phase C-18 preparative HPLC eluting with acetonitrile/water with 0.1% acetic acid from 5% to 30% with a linear gradient. After lyophilization, 3—[(R)—1 —(2,6—dichloro—3—fluoro—phenyl)—ethoxy]—5—(1—piperidin—4—yl—1 H—pyrazol—4—yl)—pyridin—2 —ylamine acetate was obtained as a white solid (410 mg, 78% yield, 100% HPLC purity, 96.4% ee). 1H NMR (DMSO—d6, 400 MHz)δ7.84 (s, 1H), 7.68 (d, 1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (q, 1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m, 2H), 1.88 (m, 2H), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e 450 (M+1)+.

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