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Example 16; Preparation of Compound 16: N-(4,6-dimethyl-2-pyridinyl)valyl-(4R)-N-((1R,2S)-1-((dimethylsulfamoyl)carbamoyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)oxy)-L-prolinamide; Step 1:; To a solution of N-Boc-vinylcyclopropane carboxylic acid (1.83 g, 8.05 mmol) and THF (32 mL) was added 1,1'-carbonyldiimidazole (1.44 g, 8.86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with N,N-dimethylsulfamide (1.0 g, 8.05 mmol) followed by DBU (2.45 g, 16.1 mmol) and was stirred at room temperature for an additional 15 hours. The reaction was then diluted with ethyl acetate (50 mL) and washed with 1.0M aqueous HCl (2.x.25 mL). The aqueous layer was extracted with ethyl acetate (2.x.50 mL). The combined organic portion was washed with H2O (25 mL) and brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (2.6 g, 97percent yield) which was used without further purification. LC-MS, MS m/z 356 (M++Na).
To a suspension of <strong>[103877-80-1]2,5-difluoro-4-methylbenzoic acid</strong> (6.0 g, 3.5 mmol) in 1,2-dichloroethane (100 mL) was added 4-dimethylaminopyridine (10.65 g, 8.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide:hydrochloride (16.65 g, 8.7 mmol) in 1 ,2- dichloroethane (60 mL) and N,N-diisopropylethylamine (15 mL, 8.60 mmol) and the mixture stirred at room temperature for 20 minutes. N,N-Dimethylsulfamide (8.64 g, 6.9 mmol) was added to the solution and the mixture heated at 60C under nitrogen. After 3 hours the mixture was cooled to room temperature and extracted with dichloromethane (100 mL). The extract was washed successively with 2M hydrochloric acid (2 x 300 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated to afford an oil (8.40 g) which solidified at room temperature. The crude product was purified by silica gel column chromatography eluting with ethyl acetate/heptane 1 :4 as eluent to afford the title compound (7.17g, 79%) as a white solid. 1 H NMR (400 MHz, CDCI3):5 2.32 (s, 3H), 3.01 (s, 6H), 7.01 (dd, 1 H), 7.65 (dd, 1 H), 8.74 (br s, 1 H). LCMS Rt = 2.10 minutes MS m/z 277 [M-H]"
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