FIELD: medicinal chemistry.
SUBSTANCE: method for preparing crystalline anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino) -2-butenamide in the form of maleate salt, including the following steps: 1) heating (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and maleic acid up to 50-60°C water in solution: n-propanol and keeping the mixture at 50-60°C; 2) cooling the specified solution to 40°C and keeping the cooled solution at 40°C for 12 hours; 3) additional cooling of the cooled solution to room temperature 25°C and keeping the additionally cooled solution at room temperature 25°C; 4) filtering the mixture obtained in step 3) to obtain crystalline maleate salt (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6- quinolinyl}-4-(dimethylamino)-2-butenamide, where the crystalline maleate salt is (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6 -quinolinyl}-4-(dimethylamino)-2-butenamide is the monohydrate of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6- quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Form II, wherein (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy monohydrate -6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Form II, is characterized by X-ray diffraction peaks at the following 2θ-corners (± 0.20°) in its X-ray diffraction pattern: 6.53, 8.43, 10.16, 12.19, 12.47, 13.01, 15.17, 16.76, 17.95, 19.86, 21.11, 21.88, 23.22, 23.78, 25.69, 26.17, 27.06, 27.5 8, 28.26, 28.73 and 29.77; and 5) drying monohydrate (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Form II, from step 4) in vacuum at a temperature of 40 to 60°C for 12 to 48 hours to give crystalline anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Form I, wherein crystalline anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6- quinolinyl}-4-(dimethylamino)-2-butenamide maleate, Form I, is characterized by X-ray diffraction peaks at the following 2θ-corners (±0.20°) in its X-ray diffraction pattern containing 6.16, 7.38, 8.75, 12.61, 14.65, 15.75.
EFFECT: new method for producing crystalline anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide as a maleate salt, which may be useful in the treatment of cancer.
6 cl, 11 tbl, 2 ex, 8 dwg
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