Hydrochloric Acid → HCID 46914737, compound

Participants

Reaction Steps

To a solution of diisopropylamine (0.0772 mL, 0.551 mmol) in tetrahydrofuran (1.5 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.206 mL, 0.514 mmol). After 10 minutes, a solution of (3S,3aR)-methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate, Example 93 (159 mg, 0.367 mmol) in tetrahydrofuran (3.0 mL) was added dropwise. After 1 hour at −78° C., iodomethane (0.0343 mL, 0.551 mmol) was added. The reaction was kept at −78° C. and monitored by LCMS. After 2 hours, another 0.015 mL of iodomethane was added. Lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 0.100 mL, 0.100 mmol) was added, followed by another 0.015 mL iodomethane. Allowed to slowly warm to room temperature overnight. The reaction was treated with 0.5 mL methanol and 0.5 mL 2.5 N NaOH. After 4 hours, the reaction mixture was neutralized with 0.5 mL of 3 N hydrogen chloride and concentrated under a stream of nitrogen. The residue was dissolved in dimethylformamide/methanol, filtered through a syringe filter and purified by reverse-phase HPLC (60 to 95% acetonitrile/water/0.05% trifluoroacetic acid) to give the title compound (yellow solid, 48.6 mg, 0.112 mmol, 30.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s., 1H), 8.10 (d, J=8.2 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.57 (d, J=5.9 Hz, 1H), 3.01-3.10 (m, 2H), 1.91-2.11 (m, 3H), 1.71-1.82 (m, 1H), 1.09-1.56 (m, 7H), 1.06 (s, 3H). ES-MS m/z 434 (M+H).

Provenance & Evidence