Pharmaceutical composition containing FGFR4 inhibitor

[0337] Preparation of intermediates

[0338] Intermediate 1: Preparation of 6-amino-4-fluoronicotine nitrile

[0339]

[0340] The first step: the preparation of 4-fluoro-5-iodopyridin-2-amine

[0341]

[0342] 4-fluoropyridin-2-amine (9g, 80mmol), NIS (19.8g, 88mmol), TFA (3.65g, 32mmol) were mixed in MeCN (290mL), and reacted overnight at room temperature. Diluted with ethyl acetate (300 mL), saturated with Na 2 SO 3 The aqueous solution (150 mL×2) was washed, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 4-fluoro-5-iodopyridin-2-amine (15.8 g, 83%).

[0343] MS m / z(ESI):238.9[M+H] + .

[0344] The second step: the preparation of 6-amino-4-fluoronicotine nitrile

[0345]

[0346] 4-Fluoro-5-iodopyridin-2-amine (15.8g, 66.4mmol), Zn(CN) 2 (8.2g, 69.8mmol), Zn (0.87g, 13.3mmol) were mixed in DMA (55mL), and Pd was added under nitrogen atmosphere 2 (dba) 3 (2.4g, 2.62mmol) and...

[0694] N-(5-cyano-4-(((trans)-2-methoxycyclopentyl)amino)pyridin-2-yl)-7-formyl-6-((3-carbonylmorpholino )methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

[0695]

[0696] The first step: N-(5-cyano-4-(((trans)-2-methoxycyclopentyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)- Preparation of 6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

[0697]

[0698] 6-amino-4-(((trans)-2-methoxycyclopentyl)amino)nicotine nitrile (20mg, 0.09mmol), phenyl 7-(dimethoxymethyl)-6-(( 3-Carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (38 mg, 0.09 mmol) was mixed in THF (5 mL), N 2 Under the atmosphere, it was cooled to -78°C, a solution of LiHMDS in THF (0.2 mL, 0.2 mmol) was added dropwise, and the reaction was allowed to rise to room temperature overnight. Add saturated NH 4 Cl aqueous solution (50mL), extracted with ethyl acetate (50mL×2), the organic phase was washed with saturated brine, dried over anhydrous sodium s...

[0706] (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1 ,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

[0707]

[0708] The first step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide synthesis

[0709]

[0710](R)-6-amino-4-((1-methoxypropan-2-yl)amino)nicotine nitrile (30mg, 0.14mmol), phenyl 7-(dimethoxymethyl)-6-( (2-Carbonyl-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthalene-1(2H)-carboxylate (60mg, 0.13 mmol) was dissolved in THF (5mL), N 2 Cool to -78°C under atmosphere, add a solution of LiHMDS in THF (0.3mL, 0.3mmol) dropwise to the reaction solution, and let it rise to room temperature to react overnight. Add saturated NH 4 Cl aqueous solution (50mL), extracted with ethyl acetate (50mL×2), the combined organic phases were washed with saturated brine, dried over anhydrou...