Maleate salts of (E) -N- {4- [3-Chloro-4- (2-pyridinylmethoxy) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethylamino) -2-butenamide and its crystalline forms
LU, Qinhong,KU, Mannching Sherry,CHEW, Warren,CHEAL, Gloria Karen,HADFIELD, Anthony F.,MIRMEHRABI, Mahmoud
申请号：
ES13150913
公开号：
ES2612273T3
申请日:
2008.10.16
申请国别(地区):
ES
年份:
2017
代理人:
摘要：
A method for preparing (E) -N- {4- [3-chloro-4- (2-pyridinylmethoxy) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethylamino) -2-butenamide partially hydrated as a maleate salt comprising the steps of: i) heating (E) -N- {4- [3-chloro-4- (2-pyridinylmethoxy) anilino] -3-cyano-7-ethoxy-6- quinolinyl} -4- (dimethylamino) -2-butenamide and maleic acid at 50 ° C-60 ° C in a water solution: n-propanol and keep the mixture at 50-60 ° C for a minimum of 15 min； ii) cooling said solution for at least one hour at 40 ° C and keeping the solution cooled to 40 ° C for 12 hours； iii) further cooling the cooled solution to room temperature, 25 ° C, for a minimum of 4 hours and keeping the solution further cooled to room temperature, 25 ° C, for at least 2 hours； iv) filter the mixture obtained in step iii) to obtain (E) -N- {4- [3-chloro-4- (2- pyridinylmethoxy) anilino] -3-cyano-7-ethoxy-6 maleate salt -quinolinyl} -4- (dimethylamino) -2-crystalline butenamide, where the (E) -N- {4- [3-chloro-4- (2-pyridinylmethoxy) anilino] -3-cyano-7 maleate salt -ethoxy-6-quinolinyl} -4- (dimethylamino) -2- crystalline butenamide is (E) -N- {4- [3-chloro-4- (2-pyridinylmethoxy) anilino] -3-cyano-7 maleate -ethoxy-6- quinolinyl} -4- (dimethylamino) -2-butenamide monohydrate； v) drying the (E) -N- {4- [3-chloro-4- (2-pyridinylmethoxy) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethylamino) -2 maleate -butenamide monohydrate from step iv) under vacuum at a temperature above 30 ° C for 12 to 48 hours to obtain (E) -N- {4- [3-Chloro-4- (2-pyridinylmethoxy) anilino] maleate] -3-cyano-7-ethoxy-6- quinolinyl} -4- (dimethylamino) -2-butenamide anhydrous crystalline； and vi) exposing the (E) -N- {4- [3-chloro-4- (2-pyridinylmethoxy) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethylamino) - maleate Anhydrous crystalline 2-butenamide at a relative humidity of 75% at room temperature (20-25 ° C) for 22 days, to form (E) -N- {4- [3-Chloro-4- (2-pyridinylmethoxy) maleate ) anilino] -3-cyano-7-
