Aluminium lithium hydride → N-(1-{[3-(aminomethyl)phenyl]methyl}-4-chloro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide

Participants

Reaction Steps

To an ice/water bath cooled solution of 5-chloro-N-{4-chloro-1-[(3-cyanophenyl)methyl]-1H-indazol-3-yl}-2-thiophenesulfonamide (for a preparation see Intermediate 42) (95 mg, 0.20 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen atmosphere was added dropwise over 1 min lithium aluminium hydride (1M solution in diethyl ether, 0.513 mL, 0.513 mmol). The reaction was stirred in the ice/water bath for 10 min, and then at room temperature for 30 min. Reaction re-cooled in the ice/water bath and a further portion of lithium aluminium hydride (1M solution in diethyl ether, 0.2 mL) was added dropwise over 1 min. Reaction stirred at room temperature for 1.5 h, then cooled (ice/water bath) and cautiously quenched with water (dropwise) until no more effervescence. The reaction mixture was then diluted with 1:1 methanol-dichloromethane in order to try to improve solubility and applied to a methanol pre-conditioned 20 g SCX-2 cartridge. The cartridge was washed with methanol and then eluted using 2M ammonia in methanol solution. The 2M ammonia in methanol fractions were combined and evaporated in-vacuo to yield N-(1-{[3-(aminomethyl)phenyl]methyl}-4-chloro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (68 mg, 0.15 mmol) as an off-white solid. This amine was dissolved in DMF (2 mL) and added to a mixture of HATU (99 mg, 0.16 mmol), acetic acid (8.3 μL, 0.14 mmol), N,N-diisopropylethylamine (0.076 mL, 0.44 mmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at room temperature for 4 h, partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine-water (1:1), passed through a hydrophobic frit and evaporated in-vacuo to yield a yellow oil, which was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by Mass Directed AutoPreparative HPLC (Sunfire C18 column 150 mm×30 mm i.d. 5 μm packing diameter at ambient temperature) eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) over 25 min. Appropriate fraction was evaporated in-vacuo to yield the title compound as a yellow oil (6.7 mg, %). LCMS (System B) RT=2.66 min, ES+ve m/z 509/511 (M+H)+.

Provenance & Evidence