Afatinib Impurity 19 synthesis

Yield:-

Reaction Conditions:

in ISOPROPYLAMIDE;water at 0;

Steps:

A.1.1.1

To a stirred solution of the above crude (2E)-4-brorno-N-[4-(3-chloro-4-fluoroanilino)-7-methoxy- 6-quinazolinyl]-2-butenamide (1.0 g, 2.15 mmol) in dimethylacetamide (35 mL) at 0 °C was added excess aqueous dimethylamine solution (40 %, 5 mL). After 3 hours the reaction was diluted with brine and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Chromatography on silica gel elutingwith dichloromethane/methanol (5:95 to 15:85) then gave (2jE)-N-[4-(3-chloro-4- fluoroanilino)-7-methoxy-6-quinazolmyl]-4-(dirned3ylamino)-2-butenaniide (14) (0.74 g, 80%) as a white solid, m.p. (MeOH) 179-181°C. ¹H NMR [(CD_j)₂SO] δ 9.78 (s, 1 H), 9.64 (s, 1 H), 8.93 (s, 1 H), 8.53 (s, 1 H), 8.13 (ddj = 2.6, 6.9 Hz, 1 H), 7.83-7.79 (m, 1 H), 7.42 (ddj = 9.1 Hz, J_HF = 9.1 Hz, 1 H), 7.29 (s, 1 H), 6.80 (pi, J = 6.0, 15.4 Hz, 1 H), 6.58 (dj = 15.4 Hz, 1 H), 4.01 (s, 3 H), 3.08 (d J = 6.0 Hz, 2 H), 2.19 (s, 6 H). Analysis found: C, 56.32; H, 5.14; N, 15.73. C₂₁H₂₁ClFN₅O₂-H₂O requires: C, 56.32; H, 5.18; N, 15.64.

References:

WO2010/104406,2010,A1 Location in patent:Page/Page column 34; 43-44