Citric Acid → N-((S)-1-(5-amino-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

Participants

Reaction Conditions

Reaction Steps

Compound 49B (60 mg, 0.1 mmol) was dissolved in 1 mL of DMF and cooled to 0° C. To it was added N,N-diisopropylethylamine (0.09 mL, 0.5 mmol) followed by a solution of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (26 mg, 0.1 mmol) and HATU (56.5 mg, 0.15 mmol) in 1 mL of DMF. To it was added 0.5 mL of ethanol and 0.1 mL of 15% NaOH aqueous solution and stirred for 5 min. The reaction mixture was acidified with 5% citric acid and then extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ 8.23 (dd, 1H), 7.09 (q, 1H), 6.97 (d, 1H), 6.83-6.53 (m, 2H), 6.37 (m, 2H), 6.17 (d, 1H), 4.80-4.66 (m, 3H), 3.38 (s, 2H), 3.06 (dd, 1H), 2.97 (d, 4H), 2.91 (m, 1H), 2.55-2.42 (m, 2H), 1.44-1.34 (m, 1H), 1.12-1.00 (m, 1H). MS (m/z) 753.14 [M+H]+.

Provenance & Evidence