Water → N-{[(3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-yl]Methyl}-N-{[(2S)-8-methyl-2,3-dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]methyl}amine

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Reaction Conditions

Reaction Steps

Butyronitrile (1.71 kg) was charged to a (5.0 L) cylindrical reactor equipped with an overhead stirrer, temperature controller, thermocouple, and reflux condenser (reactor A). To the reaction vessel, under nitrogen was charged sequentially, {[(3S)-6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]methyl}-amine (180 g, 0.82 mole) (Example 92), potassium carbonate (110.5 g. 0.8 mole) and quinaldine brosylate (400.8 g, 0.9 mole) (prepared according to the procedure described in U.S. Pat. No. 6,693,197 B1). The slurry was heated with stirring under positive nitrogen pressure to 95±5° C. for 27 h. After completion of the reaction, the mixture was cooled to 22±5° C. Water (1100 mL) was charged and stirred for 10 min. The layers are separated and the aqueous layer discarded. Ammonium chloride solution was added and stirred. The layers are separated and the organic phase was washed once more with ammonium chloride solution (2% aqueous, 1100 mL). The layers were separated and the organic phase warmed to 40±5° C. in reactor A. A solution of maleic acid (119 g, 1.02 moles) in 2-propanol (0.7 L) was prepared by warming to 40±5° C. in a separate (2-L) reactor (reactor B). The warm maleic acid solution was added slowly to the butyronile solution in reactor A maintaining the temperature between 40 to 45° C. The solution was slowly cooled 20 to 25° C. and stirred for 16 h when solids separated out. The solids were filtered through a funnel lined with polypropylene and washed with 2-propanol (0.60 L). The wet solids from the funnel were transferred to ethanol (grade 2B, 2.5 L) in reactor A and warmed to 40 to 45° C. with stirring for 30 min. The slurry was cooled to 22 to 25° C. and stirred for an additional 2 h. The solids were filtered through a funnel lined with polypropylene and washed with ethanol (grade 2B, 1.7 L). The solid was dried under vacuum (<20 mm Hg) at 40° C. to give 330 g of maleic acid salt of N-{[(3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-yl]Methyl}-N-{[(2S)-8-methyl-2,3-dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]methyl}amine (73% yield). Purity by HPLC is 97.4% (diastereomer content 2.1%), MW 431 (LC/MS).

Provenance & Evidence