Sodium Hydroxide → 1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride dihydrate

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Reaction Steps

A 5N sodium hydroxide aqueous solution (40 ml) was added at room temperature to a solution of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride (20 g) in tetrahydrofuran (200 ml) and stirred for 2 hours and 42 minutes. After completion of the reaction, the reaction mixture was allowed to stand and the layers were separated. The obtained organic layer was added dropwise over a period of 1 hour and 5 minutes at room temperature to a suspension solution of acetone (200 ml), water (20 ml), 35% hydrochloric acid (16 ml) and seed crystals (0.2 g) of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride dihydrate obtained by the method described in Example 8-2 in WO 2008/026577. The mixture was stirred for 2 hours and 28 minutes at room temperature, and after confirming the crystal precipitation, acetone (100 ml) was added and the mixture was further stirred for 1 hour and 25 minutes. The obtained solid was collected by filtration and dried to give 19.2 g of the title compound.

Provenance & Evidence