Acetic Acid → p-Toluenesulfonic acid monohydrate

Participants

Reaction Conditions

Reaction Steps

Stage 3—5-{4-[(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]-6-quinazolinyl}-2-furancarbaldehyde 4-methylbenzenesulfonate (1 wt) and 2-(methylsulfonyl)ethylamine hydrochloride (0.4 wt, 1.60 equiv.) are suspended in THF (10 vols). Sequentially, acetic acid (0.354 vol., 4.00 equiv.) and di-isopropylethylamine (DIPEA, 1.08 vols, 4.00 equiv.) are added. The resulting solution is stirred at 30°-35° C. for ca. 1 hour then cooled to ca. 22° C. Sodium tri-acetoxyborohydride (0.66 wt, 2.00 equiv.) is then added. The resulting mixture is stirred at ca. 22° C. for 2-4 hours then sampled for HPLC analysis. The reaction is quenched by addition of aqueous sodium hydroxide (25% w/w, 3 vols.) followed by water (2 vols.). The aqueous phase is then separated, extracted with THF (2 vols) and the combined THF extracts are then washed twice with 25% w/v aqueous ammonium chloride solution (2×5 vols). A solution of p-toluenesulfonic acid monohydrate (p-TSA, 0.74 wt, 2.5 equiv.) in water (1 vol) is prepared, warmed to ca. 60° C., and N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4-methylbenzenesulfonate hydrate seeds are added. The THF solution of the free base is added to the p-TSA solution over at least 1 hr, maintaining the batch temperature at 60±3° C. The resulting suspension is stirred at ca. 60° C. for 1-2 hours, cooled to 20-25° C. over an hour and aged at this temperature for ca. 1 hr. The solid is collected by filtration, washed with 95:5 THF: Water (3×2 vols) and dried in vacuum at ca. 35° C. to give N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4-methylbenzenesulfonate hydrate as a bright yellow crystalline solid.

Provenance & Evidence