The preparation method of alk inhibitor brigatinib
A technology of tini and solvent, which is applied in the field of intermediates and impurities in the preparation process, can solve the problems of low reaction yield, expensive raw materials, and no specific impurities, so as to achieve easy access to reaction raw materials, convenient post-processing, and avoid The effect of passing through the column
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Embodiment 1
[0048] Synthesis of Intermediate 1 (2,5-dichloro-N-(2-(dimethylphosphino)phenyl)pyrimidin-4-amine).
[0049]
[0050] 2,4,5-Trichloropyrimidine (AP-2) (15.2 g, 83 mmol), 2,4,5-trichloropyrimidine and 2-(dimethyloxophosphoryl)aniline (AP-1) (9.4 g, 55.6 mmol,) and K 2 HPO 4 (15.3 g, 110 mmol) in a suspension in DMF (55 mL) and stirred at 65°C for 4 hours. After cooling, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (20 ml), and the filtrate was evaporated. The residue was dissolved in ethyl acetate (50ml), extracted three times with saturated sodium chloride solution (3×100ml), the organics were combined and concentrated by rotation to a yellow-white solid, which was slurried three times with PE (3×20ml) to obtain the obtained solution. The desired product, 12.0 g AP-3, was a yellow-white solid. Yield: 90.3%, HPLC purity >98.0%. ESI-MS(m / z): 316.0[M+H] + ,631.0[2M+H] +
Embodiment 2
[0052] Synthesis of 1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)4-methylpiperazine
[0053]
[0054] 2-Nitro-5-fluoroanisole (17.1 g, 0.1 mol) and 1-methyl-4-(4-piperidinyl)-piperazine (18.3 g, 0.1 mol) in MeCN (65 mL) solvent , potassium carbonate (27.6 g, 0.2 mol) was used as an acid dressing agent, refluxed and stirred for 4.5 hours, cooled to room temperature, filtered with suction, and the filter cake was washed with DCM (20 mL). The filtrates were combined and concentrated, the concentrated solid was dissolved in DCM (50ml), extracted three times with 1 mol / L HCl solution (3×15ml), the aqueous layer was collected and adjusted to pH=8.0 with potassium carbonate, then extracted three times with DCM (3×20ml) . Dry over sodium sulfate, filter, and concentrate in vacuo to give the desired product AP-6 as a bright yellow powder 29.34 g, yield 87.8%, HPLC purity >99.8%. ESI-MS(m / z): 335.2[M+H]+, 669.4[2M+H]+
Embodiment 3
[0056] Synthesis of Intermediate 2(2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperazinyl]-aniline)
[0057]
[0058] 1-(1-(3-Methoxy-4-nitrophenyl)piperidin-4-yl)4-methylpiperazine (AP-6) (20 g, 0.06 mol) was dissolved in EtOH (800 mL) After neutralization, catalytic hydrogenation (10 psi H 2 ) 2.5 hours. The mixture was filtered through celite and the filtrate was concentrated to give a purple solid. Yield: 17.3 g, 95% yield, >99.8% purity. ESI-MS(m / z): 305.2[M+H]+609.4[2M+H]+
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