2,6-Lutidine → (R)-N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide

Participants

Reaction Conditions

Reaction Steps

In a round bottom flask was placed 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 54 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (88 mg, 77%) as a yellow foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C26H38N3O5SSiCl (M+H)+ 568.2063, observed 568.2063; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.51 (m, 1H, CH), 1.79-2.29 (m, 8 H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.84 (m, 2H, OCH2), 3.96 (m, 1H, ArCHCO), 3.96 (m, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.61 (dd, Jo=8.2 Hz, Jm=1.4 Hz, 1H, Ar), 7.73 (d, Jm=1.4 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).

Provenance & Evidence