Process for preparing alectinib
一种艾乐替尼、化合物的技术，应用在中间体化合物的制备领域，能够解决昂贵、有毒试剂、总产率低等问题
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Embodiment 1
[0137] Prepared in three steps, the compound of formula III is isolated
[0138] steps a and b
[0139]
[0140] step c
[0141]
[0142] Step a - Alkynylation: Preparation of Compound 9-(trimethylsilyl)ethynyl-6,6-dimethyl-8- (4-morpholin-4-ylpiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (III)
[0143] In a dry Schlenk tube, the reactants were added under nitrogen in the following order: Compound IV (1.07 g, 2 mmol), PdCl 2 (PPh 3 ) (2mol%), trimethylsilylacetylene (2.5eq, 712μL), TEA (2eq, 558μL) and DMF (13mL). Close the Schlenk tube and transfer to an 80 °C oil bath. The reaction was stirred until complete conversion of compound IV (8-12 hours). The reaction mixture was cooled at room temperature, filtered on charcoal and washed with DMF (2 x 5 mL). Water (60 mL) was added to the crude reaction product to give a yellow precipitate which was filtered, washed with water (3 x 10 mL) and dried under vacuum (74% yield, 816 mg).
[0144]...
Embodiment 2
[0155] Prepared in two steps without isolating the compound of formula III
[0156]
[0157] Step a-b - Alkynylation and Cleavage: Preparation of Compound of Formula II
[0158] In a dry Schlenk tube, the reactants were added under nitrogen in the following order: Compound IV (1.07 g, 2 mmol), PdCl 2 (PPh 3 ) (2mol%), trimethylsilylacetylene (2.5eq, 712μL), TEA (2eq, 558μL) and DMF (13mL). Close the Schlenk tube and transfer to an 80 °C oil bath. The reaction was stirred until complete conversion of compound IV. The tube was removed from the oil bath and the reaction mixture was filtered on charcoal and washed with DMF (2 x 5 mL). Then MeOH (15mL) and K 2 CO 3 (3eq., 614mg) was added to the DMF solution, and stirring was continued at room temperature until the reaction was complete. Water (60 mL) was slowly added to the reaction crude product to give a yellow precipitate which was filtered, washed with methanol (3 x 10 mL) and dried under vacuum (717 mg, 1.50 mmol,...
Embodiment 3
[0162] One-pot preparation of alectinib
[0163]
[0164] In a dry Schlenk tube, the reactants were added under nitrogen in the following order: Compound IV (160 mg, 0.3 mmol), PdCl 2 (PPh 3 ) (4.3 mg, 2 mol%), trimethylsilylacetylene (106 μL, 2.5 eq.), TEA (85 μL, 2 eq.) and DMF (13 mL). Close the Schlenk tube and transfer to an 80 °C oil bath. The reaction was stirred until complete conversion of the reactants. Remove the tube from the oil bath and cool at room temperature. Under nitrogen, MeOH (1 mL) and K 2 CO 3 (125mg, 3eq.), and the reaction was stirred for 2 hours. The solution was transferred to an autoclave, and THF (4 mL) and Pd / C 10% (10 mol%, 31 mg) were added to the reaction mixture. Fill the autoclave with H at a pressure of 2.5 bar 2 And the reaction was stirred for 8 hours.
[0165] Hydrogen gas was released from the reactor, and the reaction mixture was filtered onto a pad of celite and transferred to a flask. The solvent was evaporated in vacuo. W...
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