A bcr-abl kinase inhibitor
A kinase inhibitor, C1-C8 technology, used in cancer and other cell proliferative diseases, BCR-ABL tyrosine kinase inhibitor, the treatment of diseases mediated by BCR-ABL kinase activation, can solve the problem of failure. Effective treatment of problems such as CML
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[0089] Compound preparation
[0090] Compounds of formula (I) may be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. Additionally, solvents, temperatures and other reaction conditions given herein may be varied according to the skill in the art. As a further guide, the following synthetic methods can also be utilized.
[0091]The reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments which are subsequently added by methods described herein and / or methods known in the art.
[0092] In certain embodiments, provided herein are methods of making and methods of using the BCR-ABL kinase inhibitor compounds described herein. In certain embodiments, the compounds described herein can be synthesized using the following synthetic schemes. Compounds can be synthesized using methods similar to those de...
Embodiment 1
[0107] Synthesis of compounds of the present invention
[0108] plan 1
[0109]
[0110] Ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (2): In a round bottom flask was added ethyl 4-chloro-2-(methylthio)pyrimidinecarboxylate (1.0 g) Then tetrahydrofuran THF (10 mL), methylamine hydrochloride (0.58 g) were added. Then triethylamine TEA (2.1 mL) was added. The reaction system was reacted at room temperature under argon protection for 14 hours. After the reaction, the system was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain the crude product, MS (ESI) m / z (M+H) + :228.07.
[0111] 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (3): add ethyl 4-(methylamino)-2-(methylthio)pyrimidin...
Embodiment 2
[0121]
[0122] tert-Butyl 2-methyl-5-nitrophenylamide (15): Add 2-methyl-5-nitroaniline (10.0 g), tetrahydrofuran (50 ml), (Boc) 2 O (20.0 g), and 4-dimethylaminopyridine DMAP (0.3 g). The reaction system was reacted at 0°C under argon protection for 1 hour, and then the reaction system was refluxed for 12 hours. After the reaction, the system was diluted with ethyl acetate. The organic phase was washed with saturated sodium carbonate, water, and saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained after separation and purification of the organic phase. MS(ESI)m / z(M+H) + :253.01.
[0123]tert-Butyl 5-amino-2-methylphenylamide (16): In a round bottom flask was charged 15 (10.0 g), methanol (50 mL), and 10% Pd / C (1 g). The system was stirred and reacted under hydrogen for 2 hours. After the reaction is completed, filter, wash and evaporate the solvent to obtain the crude product MS (ESI) m / z (M+H) + :223.11.
[0124] tert-Butyl 4-m...
PUM
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