Tyrosine kinase inhibitors
a technology of tyrosine kinase and inhibitor, which is applied in the field of compounds and pharmaceutical compositions, can solve problems such as cell transformation leading to the development of cancer
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example 1
of 5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-amine (5′)
[0417]
Step 1-1: Synthesis of 4-(3-((4-Chloro-6-methoxyquinolin-7-yl)oxy)propyl)-morpholine (3′
[0418]A solution of 4-chloro-6-methoxyquinolin-7-ol (7.6 g, 36.3 mmol), 4-(3-chloro-propyl)morpholine (6.3 mL, 6.7 g, 40.9 mmol), potassium carbonate (15.0 g, 108.5 mmol) in DMF was allowed to stir at 90° C. for 22 h. LC / MS traces indicated the alkylation reaction is complete and hence, the mixture was cooled down to room temperature, diluted with water (240 mL) and extracted with EtOAc (5×75 mL). The combined organic layer was then washed with water (1×100 mL), brine (1×100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a brown residue. Trituration with ethyl ether provided 10.2 g (83%) of 4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine (3′) as a tan solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.60 (d, J=4.9 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.21 (t, J=...
example 2
of 8-Phenyl-3,4-dihydro-2H-1,4-ethano-1,5-naphthyridine-6-carboxylic Acid (13′)
[0421]
Synthesis of 1-(2-Amino-2-oxoethyl)pyridinium Chloride (6′)
[0422]A solution of 2-chloroacetamide (50.0 g, 524 mmol) and pyridine (41.5 g, 524 mmol) in 100 mL of acetonitrile was allowed to stir at 90° C. for 10 h. The suspension was cooled to room temperature, resulting solid filtered and washed with hexanes to provide 79.1 g (87%) of 1-(2-amino-2-oxoethyl)pyridinium chloride (6′) as a colorless solid.
Step 1: Synthesis of (Z)-2-Benzylidenequinuclidin-3-one (9′)
[0423]A solution of 3-quinuclidinone hydrochloride (7′, 50 g, 309 mmol), benzaldehyde (8′, 31.3 mL, 32.7 g, 167 5 mmol) and six pellets of sodium hydroxide in 150 mL of ethanol was allowed to reflux for 2 h. The reaction mixture was then allowed to cool down to room temperature and the resulting yellow precipitate was filtered, triturated with ethanol, filtered and dried to give 57.2 g (87%) of (Z)-2-benzylidenequinuclidin-3-one (9′) as a yell...
example 2a
of 4-Phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxylic Acid (13b′)
[0428]
Step 1: Synthesis of 4-Phenyl-4,6,7,8-tetrahydro-1H-5,8-ethanopyrido[3,2-d]pyrimidin-2(3H)-one (10a′)
[0429]To a solution of 2-benzylidenequinuclidin-3-one (9′, 57.2 g, 268 mmol) and urea (38.6 g, 643 mmol) in i-PrOH (500 mL), sodium t-butoxide (60.1 g, 535.6 mmol) was added and the resulting reaction mixture was allowed to stir at 100° C. for 3 h. After cooling to ambient temperature, the reaction mixture was poured into a flask containing water (1.5 L) and the resulting aqueous solution was extracted with 5% MeOH / DCM (3×100 mL), combined organic layers, dried (MgSO4), filtered and concentrated to provide a white solid upon trituration with ethyl ether. Residue from the mother liquor was chromatographed on silica gel eluting with DCM and 2% MeOH / DCM to provide another two batches of white solid upon trituration with i-PrOH. Combined three batches to obtain 34.9 g (51%) of 4-phenyl-4,6,7,8-tetr...
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